Method and system for the treatment of chronic copd with nebulized anticholinergic administrations

ABSTRACT

A method is provided for improving lung function in COPD by administering a muscarinic antagonist with a high efficiency nebulizer.

This application claims priority under 35 U.S.C. § 120 from U.S.nonprovisional patent application Ser. No. 12/393,709, filed. Feb. 26,2009, and claims priority under 35 U.S.C. § 119(e) from U.S. provisionalpatent application 61/031,639, filed Feb. 26, 2008, and from U.S.provisional patent application 61/080,184, filed Jul. 11, 2008, each ofwhich applications is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

Chronic obstructive airway disease (COPD) is a pulmonary (lung) diseasecharacterized by chronic obstruction of the airways. COPD encompassesemphysema and chronic bronchitis. Chronic bronchitis is diagnosed wherea patient suffers from chronic cough, mucus production, or both, for atleast three months in at least two successive years where other causesof chronic cough have been excluded. In chronic bronchitis, airwayobstruction is caused by chronic and excessive secretion of abnormalairway mucus, inflammation, and bronchospasm. Often chronic bronchitisis exacerbated by frequent or chronic infection.

Emphysema involves the destruction of elastin in terminal bronchioles,which leads to remodeling, destruction and ultimate collapse of theairway walls. Patients with emphysema gradually lose the ability toexhale, causing a rise in blood waste gasses (such as carbon dioxide), adrop in blood oxygen, and a general degradation of patient stamina andoverall health. A characteristic of emphysema is permanent loss ofalveoli. Remodeling leads to permanent enlargement of the air spacesdistal to the terminal bronchioles, and destruction of terminalbronchiole walls, though without fibrosis. Emphysema is progressive witha poor prognosis. Since there is no known method for repairing elastinor restoring the alveoli, therapy is generally palliative andpersistent.

Most patients suffering from COPD have both emphysema and chronicbronchitis. The standard of treatment for COPD includes maintenanceand/or rescue dosing of bronchodilator and/or anti-inflammatory aerosoldrugs. While most patients respond to treatment with metered doseinhalers or dry powder inhalers, there is a subset of patients for whomsuch options are not well-suited. Older and sicker CORD patients, forexample, often find it difficult to use, or do not experiencetherapeutic benefit from the use of, metered dose inhalers or dry powderinhalers.

Dry powder inhalers are generally passive delivery devices, whichpatients actuate by forceful, controlled inhalation through the mouth.Metered dose inhalers, on the other hand, are in general active deliverydevices, which create an atomized mist by forcing a drug solution orsuspension through a nozzle under pressure. A patient activates themetered dose inhaler by pressing an actuator and simultaneouslybreathing in through the mouth in order to deposit the drug in thepatient's lungs. Patients whose motor skills are impaired or not fullydeveloped will often have trouble activating the device, coordinatingtheir breathing, and generally using metered dose inhalers. Patients whoalso have poor inhalation capacity and control find dry powder inhalersto be difficult to operate as well. Newer inhaler devices that arebreath-actuated or produce a soft mist are easier for patients tooperate; but these newer devices still require coordination and abreath-hold; and achievement of sufficient lung deposition anddistribution is reliant on only one or two inhalations. For sicker andolder COPD patients, nebulizer delivery of their medicines is animportant delivery option, since they can generally receive a full doseregardless of disease state, because all that is required is normal(tidal) breathing over multiple minutes.

There are two general categories of bronchodilators muscarinicantagonists and beta 2-adrenergic agonists. Muscarinic antagonists arepreferred and are recommended first-line therapy for maintenancetreatment of moderate to severe COPD. Long-acting muscarinic antagonists(so-called LAMAS) are preferred to short-acting muscarinic antagonists,due to their superior efficacy and duration of effect. One LAMA that hasbeen approved for use in cam in the United States is tiotropium bromidepowder for inhalation (Spiriva®, NDA No. 021395, Boehringer Ingelheim).Tiotriopium bromide is available commercially only as a dry powder,which is administered by a breath-activated inhaler. A similar mode ofadministration is disclosed by Bannister et al. (U.S. Pat. No.7,229,607) for administration of glycopyrronium bromide (glycopyrrolate)as a dry powder. The '607 patent claims a method for achieving graterthan 20 hours of bronchodilation in a COPD patient by means of coatedparticles in a dry powder formulation. The '607 patent distinguishesthis methodology from administration of a solution formulation ofglycopyrrolate, which is characterized as being unable to achieveeffective treatment of COPD for longer than 12 hours. For example,Bannister et al. state: “Schroeckenstein et al., J. Allergy Clin.Immunol., 1988; 82(1): 115-119, discloses the use of glycopyrrolate inan aerosol formulation for treating asthma. A single administration ofthe metered-dose glycopyrrolate aerosol achieved bronchodilation over a12 hour period.” Additionally, Bannister et al. admit: “Skorodin, ArchIntern, Med, 1993; 153: 814 828, discloses the use of glycopyrrolate inan aerosol formulation for the treatment of asthma and COPD. It isstated that, in general, the quaternary ammonium anticholinergiccompounds have a duration of action of 4 to 12 hours. A dose of between0.2 to 1.0 mg of glycopyrrolate is recommended at 6 to 12 hourintervals.” And the inventors of the '607 patent also state: “Walker etal., Chest, 1987; 91(1): 49-51, also discloses the effect of inhaledglycopyrrolate as an asthma treatment. Again, the duration of effectivetreatment is shown to be up to 12 hours, although up to 8 hours appearsto be maximal.”

Hansel et al. (“Glycopyrrolate causes prolonged bronchoprotection andbronchodilation in patients with asthma,” 128 Chest 1974-1979 (2005))claim to have demonstrated an improvement in bronchodilation andbronchoprotection in mild-to-moderate asthmatic patients for a period ofup to 30 h with nebulized glycopyrronium bromide (glycopyrrolate).Single doses of glycopyrrolate (0.5, 1.0 and 2.0 mg/dose) wereadministered to mild-to-moderate asthmatic volunteers ages 18-60, whowere then challenged with doubling increments of methacholine dose untila >20% fall in FEV₁ was achieved. A log dose-response curve wasconstructed with these data by linear interpolation. No cleardose-response was observed for either bronchodilation orbronchoprotection. Although the authors claim to have demonstratedbronchodilation for a period of up to 30 h, the mean response in FEV₁was clinically meaningful (>10% change from pre-dose levels) only at 2hours post-dose and dropping to approximately 5% levels from 12 hthrough 30 h. This indicates that the bronchodilator response wasshort-lived and not sustainable beyond 12 hours. In the same study, theauthors demonstrated clinically meaningful bronchoprotective effect ofnebulized glycopyrrolate that was sustained up to 30 h at all doselevels. Although the bronchoprotective effect in response to a bronchialchallenge test is considered a useful surrogate test for treatment oflung diseases with airway hyperresponsiveness, such as asthma, apositive bronchoprotective test is not considered a predictive tool anduseful test in patients with COPD, because of the different diseasepathology and mechanisms involved in COPD. As outlined in the literatureand international guidelines, the airway hyperresponsiveness test is notconsidered a suitable test for use in COPD, therefore the data in asthmapatients presented by Hansel et al. cannot be extrapolated for COPD. Inany case, the authors seem to favor a breath-activated dry powderinhaler as the optimal mode of delivery. Id. at 1978. Thus, this studycan be seen as being supportive of the dry powder inhalation methodologytaught by Bannister et al. (U.S. Pat. No. 7,229,607). Hansel et al. listas conclusions that nebulized glycopyrrolate may have a sustainedduration of action and be superior to ipratropium bromide for treatmentof stable COPD. Id. at 1974. Nevertheless none of the treated patientsin Hansel, et al were identified as suffering from COPD, and no studyhas demonstrated a clinically meaningful bronchodilator response inCOPD, asthma, or any other respiratory disease with nebulizedglycopyrrolate for greater than 12 hours at any dose.

A sub-segment of the COPD population comprising the sickest and oldestpatients requires nebulizer delivery of their medicines because they areunable to satisfactorily operate a metered dose or dry powder inhaler.However, the treatment options for these patients are limited. Althoughtwo long-acting beta 2 agonist solution formulations are approved fornebulizer delivery twice daily (BID), and indicated for the maintenancetreatment of COPD symptoms, muscarinic antagonists are preferable forthe treatment of moderate to severe COPD. Also, once-daily dosing (QD)is preferable to BID. Ipratropium bromide is the only muscarinicantagonist approved for nebulizer delivery in COPD (monotherapy or incombination with albuterol), however ipratropium+/−albuterol isindicated for administration four times per day (QID); and QID dosingand long nebulization times of this short-acting agent is inconvenient,leading to poor compliance and thus sub-optimal clinical outcomes.Longer acting aerosol drugs have been demonstrated to generally be moreefficacious and result in better compliance compared to shorter actingdrugs.

There is thus a need for additional therapeutic options for thetreatment of COPD. There is a need for therapeutic options that offergreater convenience and better efficacy, especially for thesub-population of COPD patients who require nebulizer delivery. Inparticular there is a need for a nebulized muscarinic antagonist thatprovides more than 12 hours, and preferably at least 24 hours oftherapeutic benefit to COPD patients. Heretofore, no method, device orsystem has been suggested that satisfies these needs.

SUMMARY OF THE INVENTION

The foregoing and further needs are satisfied by embodiments of thepresent invention. Some embodiments provide long-acting treatment of oneor more symptoms of COPD. Embodiments described herein provide methods,devices and systems that permit relief of one or more symptoms of COPDfor a period of at least about 18 hr, preferably at least about 20hours, and more preferably at least about 24 hours, with nebulizedadministration of an antimuscarinic agent, such as glycopyrroniumbromide (glycopyrrolate). In particular embodiments set forth herein,there are provided methods, devices and systems for administration of anantimuscarinic agent, such as glycopyrrolate, via a high efficiencynebulizer. High efficiency nebulizers provide shorter treatment timesand superior lung deposition as compared to conventional nebulizers.High efficiency nebulizers can produce smaller particle sizes withtighter particle size distributions, which can result in more drugdepositing in the lungs, and less drug depositing in the oropharyngealpathway. This is particularly advantageous for delivering a muscarinicantagonist that has as a close-limiting side effect dry mouth, which canlimit the amount of drug that can be delivered to, and tolerated by, thepatient, and thereby prevent achievement of maximal duration oftherapeutic benefit. Also, smaller particles tend to penetrate morehomogenously and farther into the lungs, thereby enhancing distributionof the drug throughout the surface of the lungs and targeting a greaterproportion of muscarinic receptors that are involved in the pathogenesisof one or more symptoms of COPD. Without wishing to be bound by theory,the inventors believe that the enhanced deposition, distribution or bothof a long-acting muscarinic antagonist with a high efficiency nebulizer(as opposed to a conventional nebulizer) enhances outcomes in thetreatment of COPD. In an exemplary embodiment, a nebulizer capable ofdelivering droplets having a median particle diameter of less than about4.5 μm (especially less than about 4.0 μm) and a geometric standarddeviation (GSD) of less than about 2.0, (especially less than about 1.8)will provide more efficacious and better-tolerated treatment of COPDwith an antimuscarinic agent as compared to a conventional nebulizer.Some embodiments provide a unit dosage form adapted or adaptable foradministering a nominal dose of a muscarinic antagonist, such asglycopyrrolate, with a high efficiency nebulizer for treatment of COPD.Some embodiments provide a device comprising (1) a combination of a unitdosage form adapted or adaptable for administering a nominal dose of amuscarinic antagonist, such as glycopyrrolate, with a high efficiencynebulizer for treatment of COPD; and (2) a high efficiency nebulizer.

Furthermore, previous published reports of delivery of a glycopyrrolatesolution formulation by, nebulizer were at concentrations of no morethan 0.2 mg/ml and contained a preservative, benzyl alcohol, that is aknown lung irritant. Without wishing to be bound by theory, it isbelieved that a higher concentration of glycopyrrolate at the muscarinicreceptor level and a more selective targeting of the muscarinicreceptors (higher quantity of receptor binding) in the airways willcontribute to a faster onset and/or greater magnitude of therapeuticeffect and/or a greater duration of therapeutic effect. Additionally,eliminating the preservative enables higher or more concentrated dosesof glycopyrrolate to be delivered in a better-tolerated manner.

Some embodiments described herein provide a method of treating a patienthaving chronic obstructive pulmonary disease (COPD), comprisingadministering to the patient, with a high efficiency nebulizer, anominal dose of a composition comprising a muscarinic antagonist thatprovides the patient with a therapeutic effect for at least about 24hours. Also provided are systems for carrying out the aforementionedmethod, comprising a formulation to be nebulized and a high efficiencynebulizer. Some embodiments described herein provide a method oftreating a patient having chronic obstructive pulmonary disease (COPD),comprising administering to the patient, with a high efficiencynebulizer, a nominal dose of a composition comprising a muscarinicantagonist, wherein administering said nominal dose with said highefficiency nebulizer provides to the patient: (1) an increased magnitudeand/or duration of therapeutic effect; and (2) reduced or acceptableside effects, compared to administering the same nominal dose of themuscarinic antagonist with a conventional nebulizer. Some embodimentscomprise administering said nominal dose with the high efficiencynebulizer to the patient that results in therapeutically acceptable sideeffects. In some embodiments, the method comprises administering saidnominal dose of the composition with the high efficiency nebulizer tothe patient that results in reduced side effects compared toadministering the same nominal dose with a conventional nebulizer. Insome embodiments, the method comprises administering said nominal doseof the composition with the high efficiency nebulizer produces acalculated respirable dose of the muscarinic antagonist, whereby thepatient experiences reduced side effects compared to administering anominal dose that is calculated to achieve the same respirable dose witha conventional nebulizer. In some embodiments, the method comprisesadministering said nominal dose of the composition with the highefficiency nebulizer achieves a deposited lung dose of the muscarinicantagonist, whereby the patient experiences reduced side effectscompared to administering a nominal dose that achieves substantially thesame deposited lung dose with a conventional nebulizer. In someembodiments, the composition comprising the muscarinic antagonist is aconcentrated, preservative-free, pH-adjusted solution formulation of themuscarinic antagonist. In some embodiments, e.g. when the muscarinicantagonist is glycopyrrolate, the concentration of the muscarinicantagonist is about 25 to about 400 μg/mL. In some embodiments, thecomposition has a pH of 3 to 5. In some embodiments, the formulation isroom temperature stable for at least 2 years. In some embodiments, thecomposition comprising the muscarinic antagonist contains about 50 μg toabout 1000 μg of glycopyrrolate as the muscarinic antagonist. In someembodiments, the composition has a volume of about 1.0 mL or less, e.g.0.1 to 1.0 mL (especially 0.3 to 0.7 mL) or 0.5 mL. In some embodiments,the composition is administered in about 3 minutes or less. In someembodiments, the solution has a stabilizing excipient. In someembodiments, the stabilizing excipient is ethylenediaminetetraaceticacid (EDTA) or a pharmaceutically acceptable salt thereof. In someembodiments, the composition further comprises an excipient to mitigateside effects, for example dry mouth. In some embodiments, the excipientcomprises citric acid or a pharmaceutically acceptable salt thereof. Insome embodiments, the muscarinic antagonist is a long-acting muscarinicantagonist. In some embodiments, the nominal dose of the compositioncomprising the muscarinic antagonist contains about 25 μg to about 2000μg, about 25 μg to about 1000 μg, or about 50 μg to about 1000 μg ofglycopyrrolate as the muscarinic antagonist. In some embodiments, thenominal dose of the composition comprising the muscarinic antagonistcontains about 25 μg to about 2000 μg, about 25 μg to about 1000 μg,about 25 μg to about 500 μg, about 25 μg to about 350 μg, about 25 μg toabout 300 μg, about 25 μg to about 250 μg, about 25 μg to about 200 μg,about 50 μg to about 2000 μg, about 50 μg to about 1000 μg, about 50 μgto about 500 μg, about 50 μg to about 350 μg, about 50 μg to about 300μg, about 50 μg to about 250 μg, about 50 μg to about 200 μg, about 75μg to about 2000 μg, about 75 μg to about 1000 μg, about 75 μg to about500 μg, about 75 μg to about 350 μg, about 75 μg to about 300 μg, about75 μg to about 250 μg, about 75 μg to about 200 μg, about 100 μg toabout 2000 μg, about 100 μg to about 1000 μg, about 100 μg to about 500μg, about 100 μg to about 350 μg, about 100 μg to about 300 μg, about100 μg to about 250 μg, about 100 μg to about 200 μg, about 50 μg, about75 μg, about 100 μg, about 125 μg, about 150 μg, about 175 μg, about 200μg, about 225 μg, about 250 μg, about 275 μg, 300 μg, about 325 μg,about 350 μg, about 400 μg, about 450 μg, about 475 μg, about 500 μg,about 525 μg, about 550 μg, about 575 μg, about 600 μg, about 625 μg,about 650 μg, about 675 μg, about 700 μg, about 725 μg, about 750 μg,about 775 μg, about 800 μg, about 825 μg, about 850 μg, about 875 μg,about 900 μg, about 925 μg, about 950 μg, about 975 μg, about 1000 μg,about 1250 μg, about 1500 μg, about 1750 μg, about 2000 μg ofglycopyrrolate as the muscarinic antagonist. In some embodiments, thehigh efficiency nebulizer emits droplets having a Mass MedianAerodynamic Diameter (MMAD) of less than about 4.5 μm and a geometricstandard deviation (GSD) of less than about 2.0, or optimally an MMAD ofless than 4.0 μm and a GSD less than 1.8. In some embodiments, thetherapeutic effect comprises an improvement of FEV₁ above baseline of atleast about 10% at 24 hours after the composition is administered withthe high efficiency nebulizer. In some embodiments, the therapeuticeffect comprises an improvement of FEV₁ above baseline of at least about100 mL at 24 hours after the composition is administered with the highefficiency nebulizer. In some embodiments, the composition furthercomprises a beta 2-adrenoceptor agonist, a corticosteroid, or both 10013Some embodiments described herein provide an inhalation system for thetreatment or prophylaxis of a respiratory condition in a patient, thesystem comprising: (a) a nominal dose of a muscarinic antagonist in anaqueous inhalation solution; and (b) a high efficiency nebulizer,wherein administration of the muscarinic antagonist with the inhalationdevice provides muscarinic antagonist lung deposition (deposited orcalculated lung dose) of at least about 30%, at least about 35%, atleast about 40%, at least about 45%, at least about 50%, at least about55%, at least about 60%, about 30% to about 60%, about 30% to about 55%,about 30% to about 50%, about 30% to about 40%, about 30% to about 75%,about 40% to about 70%, or about 45% to about 60%, of the nominal doseof the muscarinic antagonist. Some embodiments provide a unit dosageform, which comprises a container that holds a nominal dose of acomposition comprising a muscarinic antagonist, such as glycopyrrolate,said container being adapted or adaptable to operate with a highefficiency nebulizer to carry out the foregoing method. Some embodimentsprovide a combination of (1) a high efficiency nebulizer and (2) theaforementioned unit dosage form.

Some embodiments described herein provide a composition foradministration with a high efficiency nebulizer, comprising aconcentrated, preservative-free, pH-adjusted solution formulation of themuscarinic antagonist. In some embodiments, the muscarinic antagonist isglycopyrrolate. In some embodiments, the glycopyrrolate formulation hasa concentration of about 50 to about 400 μg/mL. In some embodiments, theglycopyrrolate formulation has a concentration of at least 0.5 mg/mL. Insome embodiments, the glycopyrrolate has a concentration of at least 1mg/mL. In some embodiments, the pH is about 3 to about 5, and thecomposition contains a beta 2-adrenoceptor agonist (e.g. albuterol,levalbuterol, salmeterol, formoterol, or arformoterol), and/or acorticosteroid (budesonide, fluticasone, ciclesonide). In someembodiments, the composition further comprises a non-steroidalanti-inflammatory agent. In some embodiments, the composition isadministered with a high efficiency nebulizer in 2 minutes or less.

Some embodiments described herein provide a method of treating a patienthaving chronic obstructive pulmonary disease (COPD), comprisingadministering to the patient, with a high efficiency nebulizer, acomposition comprising a muscarinic antagonist that provides to thepatient a respirable dose or deposited dose of a muscarinic antagonist,wherein achievement of said respirable dose or deposited dose with saidhigh efficiency nebulizer provides to the patient: (1) a similar or anincreased magnitude and/or duration of therapeutic effect; and (2)reduced or acceptable side effects, compared to achievement of the samerespirable dose or deposited dose of the muscarinic antagonist with aconventional nebulizer. In some embodiments, achievement of therespirable dose or deposited dose with the high efficiency nebulizerproduces in the patient an increased duration of therapeutic effect ofat least 24 hours after administration of the nominal dose. In someembodiments, the therapeutic effect comprises an improvement of FEV₁ ofat least about 100 mL above baseline when adjusted for placebo or atleast about 10% above baseline, when adjusted for placebo, 24 hoursafter the composition is administered with the high efficiencynebulizer.

Some embodiments described herein provide a method of treating a patienthaving chronic obstructive pulmonary disease (COPD), comprisingadministering to the patient, with a nebulizer, a dose ofglycopyrrolate, wherein the administration produces in the patient anarea under the plasma concentration curve of glycopyrrolate (AUC) of atleast about 100 μg/mL·hr. In some embodiments, the administration of thedose of glycopyrrolate achieves in the patient a ratio of AUC to maximumplasma concentration of glycopyrrolate (Cmax) of at least about 0.6 hr,at least about 0.75 hr, at least about 1.0 hr, at least about 1.25 hr,or at least about 1.5 hr. in some embodiments, the method results in atherapeutic effect for at least about 24 hours after administering theglycopyrrolate. In some embodiments, the glycopyrrolate dose is about 25μg to about 1000 μg of glycopyrrolate. In some embodiments, theglycopyrrolate dose is about 25 μg to about 400 μg of glycopyrrolate. Insome embodiments, the therapeutic effect comprises an improvement ofFEV₁ of at least about 100 mL above baseline when adjusted for placeboor at least about 10% above baseline when adjusted for placebo 24 hoursafter the glycopyrrolate is administered with the nebulizer. In someembodiments, the nebulizer is a high efficiency nebulizer.

Some embodiments described herein provide an inhalation system for thetreatment or prophylaxis of a respiratory condition in a patient, thesystem comprising: (a) a nominal dose of a muscarinic antagonist in anaqueous inhalation solution; and (b) an inhalation device, wherein theaqueous inhalation solution provides a duration of therapeutic effect ofat least about 12 hr, about 12 hr to about 24 hr, about 18 hr to about24 hr, about 20 hr to about 24 hr or at least about 24 hr.

BRIEF DESCRIPTION OF THE DRAWINGS

Examples of aspects of the current invention are illustrated in theattached figures, of which:

FIG. 1 is a graph comparing the placebo-adjusted 24-hour (trough) FEV₁(L) obtained by, administering a 200 μg dose of glycopyrrolate with ahigh efficiency nebulizer (PART eFlow®) and a conventional jetnebulizer,

FIG. 2 is a graph comparing the placebo-adjusted 24-hour (trough) FEV₁(L) obtained by administering 25 μg, 75 μg, 200 μg, 500 μg and 1000 μgof glycopyrrolate with a high efficiency nebulizer (left 5 bars) and 200μg with a conventional jet nebulizer (right bar).

FIG. 3 is a graph comparing lung function response (FEV₁ (L) change frombaseline) over a time course of 30 hours for 200 μg of glycopyrrolateadministered with a high efficiency nebulizer, 200 μg of glycopyrrolateadministered with a conventional jet nebulizer, and placebo (saline)administered with the conventional jet nebulizer. The glycopyrrolatedose administered with the high efficiency nebulizer provided a meanimprovement in peak lung function (peak FEV₁) of about 45 mL compared tothe same glycopyrrolate dose administered in the conventional jetnebulizer. Also, the glycopyrrolate dose administered with the highefficiency nebulizer provided improvement in lung function of greaterthan 100 mL FEV₁ above baseline at the 24 hour time point, whereas thesame dose administered with the conventional jet nebulizer failed toachieve an increase in FEV₁ above baseline greater than 100 mL at anytime point after 12 hr.

FIG. 4 is a graph comparing lung function response (FEV₁ (% change frombaseline)) over a time course of 30 hours for 200 μg of glycopyrrolateadministered with a high efficiency nebulizer (left-most bar at eachtime point), 200 μg of glycopyrrolate administered with a conventionaljet nebulizer (right-most bar at each time point), and placebo (saline)administered with the conventional jet nebulizer (middle bar at eachtime point). The glycopyrrolate dose administered with the highefficiency nebulizer provided improvement in lung function of greaterthan 10% improvement in FEV₁ above baseline at the 24 hour time point,whereas the same dose administered with the conventional jet nebulizerfailed to achieve an increase in FEV₁ above baseline greater than 10% atany time point after 12 hr.

FIG. 5 is a graph comparing the area under the FEV₁ (L, above baseline)curve from 0-24 hours (AUC₀₋₂₄) obtained by administering 25 μg, 75 μg,200 μg, 500 μg and 1000 μg of glycopyrrolate with a high efficiencynebulizer (left 5 bars); and placebo and 200 μg of glycopyrrolate with aconventional jet nebulizer (right 2 bars). The AUC₀₋₂₄ results are shownin L·hr.

FIG. 6 is a graph comparing the area under the FEV₁ (L, above baseline)curve from 0-12 hours (AUC_(0-12 hrs)) obtained by administering 25 μg,75 μg, 200 μg, 500 μg and 1000 μg of glycopyrrolate with a highefficiency nebulizer (left 5 bars); and placebo and 200 ofglycopyrrolate with a conventional jet nebulizer (right 2 bars). TheAUC₀₋₁₂ results are shown in L·hr. The AUC values for the dosesdelivered by the high efficiency nebulizer achieved a similar robustmagnitude of FEV₁ improvement as the dose delivered by the conventionaljet nebulizer over the first 12 hours post-administration.

FIG. 7 is a graph comparing the area under the FEV₁ (L, above baseline)curve from 12-24 hours (AUC₁₂₋₂₄) obtained by administering 25 μg, 75μg, 200 μg, 500 μg and 1000 μg of glycopyrrolate with a high efficiencynebulizer (left 5 bars); and placebo and 200 μg of glycopyrrolate with aconventional jet nebulizer (right 2 bars). The AUC₁₂₋₂₄ results areshown in L·hr. Although the subjects that received the 200 μg dose via aconventional nebulizer achieved similar AUC FEV₁ values from 0-24 hours,and 12-24 hours, as the AUC FEV₁ values achieved by those subjects whoreceived the 25 μg dose administered by the high efficiency nebulizer,the mean AUC FEV₁ value for the FEV₁ response to the 200 μg dose via theconventional nebulizer was inferior and not clinically meaningful during12-24 hours post-dosing, whereas all doses greater than 25 μgadministered by the high efficiency nebulizer achieved robust prolongedduration of bronchodilation over the entire 24 hours.

FIG. 8 is a line graph comparing glycopyrrolate blood plasmaconcentrations during the first two hours after administration of 200 μgglycopyrrolate with a high efficiency nebulizer (upper line) and 200 μgglycopyrrolate with a conventional jet nebulizer (lower line).

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of skill in the artto which the inventions described herein belong. All publications,patents, and patent applications mentioned in this specification areherein incorporated by reference to the same extent as if eachindividual publication, patent, or patent application was specificallyand individually indicated to be incorporated by reference.

DEFINITION OF TERMS

As used herein, the term “about” is used synonymously with the term“approximately.” Illustratively, the use of the term “about” with regardto a certain therapeutically effective pharmaceutical dose indicatesthat values slightly outside the cited values, e.g. plus or minus 0.1%to 10%, which are also effective and safe.

As used herein, the terms “comprising,” “including,” “such as,” and “forexample” (or “e.g.”) are used in their open, non-limiting sense.

As used herein “mcg” means micrograms, and is synonymous with “μg” “ug”.One microgram is 0.001 mg, or 0.000001 g.

As used herein, the phrase “consisting essentially of” is a transitionalphrase used in a claim to indicate that the following list ofingredients, parts or process steps must be present in the claimedcomposition, machine or process, but that the claim is open to unlistedingredients, parts or process steps that do not materially affect thebasic and novel properties of the invention.

“Nominal dose,” as used herein, refers to the loaded dose, which is theamount of active pharmaceutical ingredient (“API”) in an inhalationdevice prior to administration to the patient. The volume of solutioncontaining the nominal dose is referred to as the “fill volume.”

“AUC_((0-t)) ^(HEN)” as used herein, refers to the area under a bloodplasma concentration curve up to the last time point for the nominaldose of active pharmaceutical ingredient (API) administered with a highefficiency nebulizer.

“AUC_((0-t)) ^(Conv)” as used herein, refers to the area under a bloodplasma concentration curve up to the last time point for a nominal doseof active pharmaceutical ingredient (API) administered with aconventional nebulizer.

“AUC_((0-∞)) ^(HEN)” as used herein, refers to the area under a bloodplasma concentration curve for a nominal dose of active pharmaceuticalingredient (API) administered with a high efficiency nebulizer.

“AUC_((0-∞)) ^(CONV)” as used herein, refers to the area under a bloodplasma concentration curve for a nominal dose of active pharmaceuticalingredient (API) administered with a conventional nebulizer [AUC_((0-∞))^(Conv)].

“Substantially the same nominal dose” as used herein, means that a firstnominal dose of an active pharmaceutical ingredient (API) containsapproximately the same number of millimoles of the muscarinic antagonistas a second nominal dose of the muscarinic antagonist.

“Bioavailability” as used herein, refers to the amount of unchanged drugthat reaches the systemic circulation. By definition, thebioavailability of an intravenous solution containing the activepharmaceutical ingredient (API) is 100%.

“Enhanced lung deposition,” as used herein, refers to an increase indrug deposition (deposited lung dose) arising out of, for example, theimproved efficiency of drug delivery with a high efficiency nebulizer.In general, a high efficiency nebulizer will produce a drug cloud havinga greater respirable fraction than a conventional nebulizer. While notwishing to be bound by theory, it is considered that a greaterrespirable fraction will permit greater lung deposition andconcomitantly lower oropharyngeal deposition of the drug. In someembodiments, it is considered that reduced oropharyngeal deposition ofdrug will reduce local side effects, for example dry mouth.

“Deposited dose” or “deposited lung dose” is the amount of muscarinicantagonist deposited in the lung. The deposited dose or deposited lungdose may be expressed in absolute terms, for example the number of μg ofAPI deposited in the lungs. The deposited lung dose may be expressed asa percentage of the nominal dose deposited in the lungs. The depositedlung dose may also be expressed in relative terms, for example comparingthe mass of API deposited in the lungs with a high efficiency nebulizerto the mass of API deposited in the lungs with a conventional nebulizer.

“C_(max) ^(HEN)” as used herein, refers to the maximum blood plasmaconcentration for a nominal dose of the active pharmaceutical ingredient(API) administered with a high efficiency nebulizer.

“C_(max) ^(Conv)” as used herein, refers to the maximum blood plasmaconcentration for a nominal dose of the active pharmaceutical ingredient(API) administered with a conventional nebulizer.

“Enhanced pharmacokinetic profile” means an improvement in somepharmacokinetic parameter. Pharmacokinetic parameters that may beimproved include, AUC_(last), AUC_((0-∞)) T_(max), and optionally aC_(max). In some embodiments, the enhanced pharmacokinetic profile maybe measured quantitatively by comparing a pharmacokinetic parameterobtained for a nominal dose of an active pharmaceutical ingredient (API)administered with one type of inhalation device (e.g. a high efficiencynebulizer) with the same pharmacokinetic parameter obtained with thesame nominal dose of active pharmaceutical ingredient (API) administeredwith a different type of inhalation device.

“Blood plasma concentration” refers to the concentration of an activepharmaceutical ingredient (API) in the plasma component of blood of asubject or patient population.

“Respiratory condition,” as used herein, refers to a disease orcondition that is physically manifested in the respiratory tract,including, but not limited to, chronic obstructive pulmonary disease(COPD), bronchitis, chronic bronchitis, emphysema, asthma, or reactiveairway disorder (RAD).

“Patient” refers to the animal (especially mammal) or human beingtreated.

“Muscarinic antagonist” refers to antimuscarinic agents, which arecompounds that have the ability to inhibit the action of theneurotransmitter acetylcholine by blocking its binding to muscariniccholinergic receptors. These agents can be long-acting or short-acting.Long-acting muscarinic antagonists have a therapeutic effect lastinggreater than about 6 hours. Some long-acting muscarinic antagonistsinclude, but are not limited to, glycopyrrolate, tiotropium, aclidinium,trospium, darotropium, QAT 370, GSK 233705, GSK 573719, GSK 656398,TD4208, BEA 218 or a pharmaceutical acceptable derivative, salt,enantiomer, diastereomer, or racemic mixture thereof. Short-actingmuscarinic antagonists have a therapeutic effect for less than about 6hours. Some short-acting muscarinic antagonists include, but are notlimited to, ipratropium, oxitropium, or a pharmaceutical acceptablederivative, salt, enantiomer, diastereomer, or racemic mixture thereof.In some embodiments, the “muscarinic antagonist” is glycopyrrolate,tiotropium, aclidinium, trospium, QAT370, GSK233705, GSK 656398,BEA2180, ipratropium, oxitropium, oxybutynin or a pharmaceuticalacceptable derivative, salt, enantiomer, diastereomer, or apharmaceutical acceptable derivative, salt, enantiomer, diastereomer, orracemic mixture thereof.

“Nebulizer,” as used herein, refers to a device that turns medications,compositions, formulations, suspensions, and mixtures, etc. into a finemist for delivery to the lungs. Nebulizers may also be referred to asatomizers.

“Drug absorption” or simply “absorption” typically refers to the processof movement of drug from site of delivery of a drug across a barrierinto a blood vessel or the site of action, e.g., a drug being absorbedin the pulmonary capillary beds of the alveoli.

[T_(max) ^(HEN)] as used herein, refers to the amount of time necessaryfor a nominal dose of an active pharmaceutical ingredient (API) toattain maximum blood plasma concentration after administration with ahigh efficiency nebulizer.

[T½] Half-life: T½ in reference to the elimination rate of a drug, suchas a muscarinic antagonist (e.g. glycopyrrolate) is the amount of timenecessary for the drug's plasma concentration to drop to one-half of itsinitial plasma concentration.

[T_(max) ^(Conv)] as used herein, refers to the amount of time necessaryfor a nominal dose of an active pharmaceutical ingredient (API) toattain maximum blood plasma concentration after administration with aconventional nebulizer.

The term “treat” and its grammatical variants (e.g. “to treat,”“treating,” and “treatment”) refer to administration of an activepharmaceutical ingredient to a patient with the purpose of amelioratingor reducing the incidence of one or more symptoms of a condition ordisease state in the patient. Such symptoms may be chronic or acute; andsuch amelioration may be partial or complete. In the present context,treatment entails administering a muscarinic antagonist (optionally incombination with a beta 2-adrenoceptor agonist) to a patient via apulmonary inhalation route.

The term “prophylaxis” refers to administration of an activepharmaceutical ingredient to a patient with the purpose of reducing theoccurrence or recurrence of one or more acute symptoms associated with adisease state in the patient. In the present context, prophylaxisentails administering a muscarinic antagonist (optionally in combinationwith a beta 2-adrenoceptor agonist) to a patient via a pulmonaryinhalation route. Thus, prophylaxis includes reduction in the occurrenceor recurrence rate of acute exacerbations in chronic obstructivepulmonary disease (COPD). However, prophylaxis is not intended toinclude complete prevention of onset of a disease state in a patient whohas not previously been identified as suffering from a pulmonarycondition or disease; nor does prophylaxis include prevention ofpulmonary cancer.

As used herein, a difference is “significant” if a person skilled in theart would recognize that the difference is probably real. In someembodiments, significance may be determined statistically—in which casetwo measured parameters may be referred to as statistically significant.In some embodiments, statistical significance may be quantified in termsof a stated confidence interval (CI), e.g. greater than 90%, greaterthan 95%, greater than 98%, etc. In some embodiments, statisticalsignificance may be quantified in terms of a p value, e.g. less than0.5, less than 0.1, less than 0.05, etc. The person skilled in the artwill recognize these expressions of significance and will know how toapply them appropriately to the specific parameters that are beingcompared.

In some embodiments described herein an active pharmaceutical ingredient(API) is a muscarinic antagonist. In some embodiments, the API issubstantially free of other bronchodilating agents, such as beta2-adrenoceptor agonists, like formoterol, salmeterol and salbutamol(albuterol). In this context, “substantially free of otherbronchodilating agents” indicates that the solution contains no otherbronchodilating agent or contains less than a quantity of anotherbronchodilating agent that would be sufficient to materially affect theproperties of the muscarinic antagonist solution. In some embodiments,the API is a muscarinic antagonist (optionally in combination with abeta 2-adrenoceptor agonist and/or in combination with ananti-inflammatory agent which could include a corticosteroid or anon-steroidal anti-inflammatory drug (NSAID)). In some embodiments, theAPI is free of other bronchodilating agents, such as beta 2-adrenoceptoragonists, like formoterol, salmeterol and salbutamol (albuterol). Inthis context, “free of other bronchodilating agents” means that thesolution contains no other bronchodilating agent than the recitedmuscarinic antagonist, or contains less than a detectable amount of theother bronchodilating agents.

Methods and Systems for the Treatment of Respiratory Conditions withHENs

The present invention provides methods and inhalation systems fortreatment or prophylaxis of a respiratory condition in a patient, suchas chronic obstructive pulmonary disease (CORD), and optionally chronicbronchitis and/or emphysema. In some embodiments, the methods andinhalation systems comprise administering to a patient a nominal dose ofan active pharmaceutical ingredient (API), muscarinic antagonist(optionally in combination with a beta 2-adrenoceptor agonist and/or incombination with an anti-inflammatory agent which could include acorticosteroid or a non-steroidal anti-inflammatory drug (NSAID)) in anaqueous inhalation solution with a high efficiency nebulizer (HEN),wherein delivering the nominal dose of the muscarinic antagonist to thepatient provides one or more of the following advantages: (1) anenhanced pharmacokinetic profile as compared to administration with aconventional nebulizer; (2) an enhanced therapeutic effect as comparedto administration with a conventional nebulizer; (4) an enhanced lungdeposition (deposited lung dose) evidenced by scintigraphy ordeconvolution, or derived from suitable in vitro indicators such asRDDR, RF, GSD, and/or a MMAD values as compared to administration with aconventional nebulizer; (5) reduced administration times, periods,and/or volumes as compared to administration with a conventionalnebulizer; (6) a reduction in adverse side effects associated with APItreatment and optionally a longer duration of therapeutic effect ascompared to administration with a conventional nebulizer; (7) optionaladministration with a beta 2-adrenoceptor agonist and optionally acorticosteroid; and (8) an enhanced method of treatment of acuteexacerbations of a respiratory condition in a patient, e.g. COPD. Insome embodiments, the methods and inhalation systems compriseadministering to a patient a nominal dose of an increased concentrationof API in an aqueous inhalation device, metered dose inhaler (MDI),conventional nebulizer, or high efficiency nebulizer.

Inhalation Therapy

An inhalation device, as used herein, refers to any device that iscapable of administering a solution to the respiratory airways of apatient. Inhalation devices include conventional inhalation devices,such as metered dose inhalers (MDIs), conventional nebulizers, such asjet nebulizers, and high efficiency nebulizers, such as vibratingmembrane nebulizers.

Inhalation nebulizers, or atomizers, are also commonly used for thetreatment of respiratory diseases. Inhalation nebulizers delivertherapeutically effective amounts of pharmaceuticals by forming anaerosol which includes droplet sizes that can easily be inhaled. Theaerosol can be used, for example, by a patient within the bounds of aninhalation therapy, whereby the therapeutically effective pharmaceuticalor drug reaches the patient's respiratory tract upon inhalation.

High Efficiency Nebulizers

High efficiency nebulizers are inhalation devices that comprise amicroperforated membrane through which a liquid solution is convertedthrough electrical or mechanical means into aerosol droplets suitablefor inhalation. High efficiency nebulizers can deliver a large fractionof a loaded dose to a patient. In some embodiments, the high efficiencynebulizer also utilizes one or more actively or passively vibratingmicroperforated membranes. In some embodiments, the high efficiencynebulizer contains one or more oscillating membranes. In someembodiments, the high efficiency nebulizer contains a vibrating mesh orplate with multiple apertures and optionally a vibration generator withan aerosol mixing chamber. In some such embodiments, the mixing chamberfunctions to collect (or stage) the aerosol from the aerosol generator.In some embodiments, an inhalation valve is also used to allow an inflowof ambient air into the mixing chamber during an inhalation phase and isclosed to prevent escape of the aerosol from the mixing chamber duringan exhalation phase. In some such embodiments, the exhalation valve isarranged at a mouthpiece which is removably mounted at the mixingchamber and through which the patient inhales the aerosol from themixing chamber. Still yet, in some embodiments, the high efficiencynebulizer contains a pulsating membrane. In some embodiments, the highefficiency nebulizer is continuously operating.

In some embodiments, the high efficiency nebulizer contains a vibratingmicroperforated membrane of tapered nozzles that generates a plume ofdroplets without the need for compressed air. In these embodiments, asolution in the microperforated membrane nebulizer is in contact with amembrane, the opposite side of which is open to the air. The membrane isperforated by a large number of nozzle orifices of an atomizing head. Anaerosol is created when alternating acoustic pressure in the solution isbuilt up in the vicinity of the membrane causing the fluid on the liquidside of the membrane to be emitted through the nozzles as uniformlysized droplets.

Some embodiments of high efficiency nebulizers use passive nozzlemembranes and a separate piezoelectric transducer that stimulates themembrane. In contrast, some high efficiency nebulizers employ an activenozzle membrane, which use the acoustic pressure in the nebulizer togenerate very fine droplets of solution via the high frequency vibrationof the nozzle membrane.

Some high efficiency nebulizers contain a resonant system. In some suchhigh efficiency nebulizers, the membrane is driven by a frequency forwhich the amplitude of the vibrational movement at the center of themembrane is particularly large, resulting in a focused acoustic pressurein the vicinity of the nozzle; the resonant frequency may be about 100kHz. A flexible mounting is used to keep unwanted loss of vibrationalenergy to the mechanical surroundings of the atomizing head to aminimum. In some embodiments, the vibrating membrane of the highefficiency nebulizer may be made of a nickel-palladium alloy byelectroforming.

In some embodiments, the high efficiency nebulizer achieves lungdeposition (deposited or calculated lung dose) of at least about 30%, atleast about 35%, at least about 40%, at least about 45%, at least about50%, at least about 55%, at least about 60%, about 30% to about 60%,about 30% to about 55%, about 30% to about 50%, about 30% to about 40%,about 30% to about 90%, about 40% to about 80%, about 50% to about 60%,or about 60% to about 70% based on the nominal dose of the muscarinicantagonist (optionally in combination with a beta 2-adrenoceptoragonist) administered to the patient. In some embodiments, the highefficiency nebulizer achieves a respirable dose delivery rate (RDDR) ofat least about 2 times, at least about 3 times or at least about 4 timesthe RDDR achievable with a conventional nebulizer. In some embodimentswhere the muscarinic antagonist is glycopyrrolate the RDDR is at leastabout 100 μg/min, at least about 150 μg/min, at least about 200 μg/min,about 100 μg/min to at least about 5,000 μg/min, about 150 μg/min toabout 4,000 μg/min or about 200 μg/min to about 3,500 μg/min. In someembodiments, Wherein the muscarinic antagonist is glycopyrrolate, thehigh efficiency nebulizer achieves an output rate of at least about 120μg/min, at least about 150 μg/min, at least about 200 μg/min or at leastabout 200 μg/min to at least about 5,000 μg/min, in some embodiments,the high efficiency nebulizer provides a respirable fraction (RF) ofmuscarinic antagonist of at least about 60%, at least about 65%, atleast about 70%, at least about 75%, at least about 80%, at least about85%, at least about 90%, about 60% to about 95%, about 65% to about 95%,about 65% to about 90% or about 70% to about 90%. In some embodiments,the high efficiency nebulizer provides a Geometric Standard Deviation(GSD) of emitted droplet size distribution of the solution administeredwith a high efficiency nebulizer of about 1.1 to about 2.1; about 1.2 toabout 2.0, about 1.3 to about 1.9, at least about 1.4 to about 1.8, atleast about 1.5 to about 1.7, about 1.4, about 1.5, or about 1.6. Insome embodiments, administration of the muscarinic antagonist with thehigh efficiency nebulizer provides a Mass Median Aerodynamic Diameter(MMAD) of droplet size of the solution emitted with the high efficiencynebulizer of about 1 μm to about 5 μm, about 2 to about 4 μm, about 3 μmto about 4 μm, about 3 to about 4 μm; or about 3.5 to about 4.0 μm. Insome particular embodiments, the high efficiency nebulizer providesdroplets having a particular combination of MMAD and GSD, for example:an MMAD of less than about 5 μm and a GSD of about 1.1 to about 2.1; anMMAD of less than about 4.5 μm and a GSD of about 1.1 to about 2.1; anMMAD of about 1 μm to about 5 μm and a GSD of about 1.1 to about 2.1; anMMAD of about 1.5 to about 4.5 μm and a GSD of about 1.1 to about 2.1;an MMAD of less than about 5 μm and a GSD of about 1.1 to about 2.0; anMMAD of less than about 4.5 μm and a GSD of about 1.1 to about 2.0; anMMAD of about 1 μm to about 5 μm and a GSD of about 1.1 to about 2.0; anMMAD of about 1.5 to about 4.5 μm and a GSD of about 1.1 to about 2.0;an MMAD of less than about 5 μm and a GSD of about 1.1 to about 1.9; anMMAD of less than about 4.5 μm and a GSD of about 1.1 to about 1.9; anMMAD of about 1 μm to about 5 μm and a GSD of about 1.1 to about 1.9; anMMAD of about 1.5 to about 4.5 and a GSD of about 1.1 to about 1.9; anMMAD of less than about 5 μm and a GSD of about 1.1 to about 1.8; anMMAD of less than about 4.5 μm and a GSD of about 1.1 to about 1.8; anMMAD of about 1 μm to about 5 μm and a GSD of about 1.1 to about 1.8; oran MMAD of about 1.5 to about 4.5 μm and a GSD of about 1.1 to about1.8.

In some embodiments; the high efficiency nebulizer provides muscarinicantagonist lung deposition (deposited or calculated lung dose) of atleast about 15%, at least about 20%, at least about 25%, at least about30%; at least about 35%, at least about 40%; at least about 45%; atleast about 50%, at least about 55%, at least about 60%, about 20% toabout 40%, about 25% to about 35%, about 25 to about 30%, about 35% toabout 90%, about 40% to about 80%, about 50% to about 60%, or about 60%to about 70% based on the nominal dose of the muscarinic antagonist. Insome embodiments; the high efficiency nebulizer provides for one or moreof (a) or (b); and one or more of (i), (ii), (iii) or (iv): (a) arespirable dose delivery rate (RDDR) of at least about 2 times; 3 timesor 4 times the RDDR achievable with a conventional nebulizer (forexample, where the muscarinic antagonist is glycopyrrolate, in someembodiments, RDDR is at least about 100 μg/min, at least about 150μg/min, at least about 200 μg/min, about 100 μg/min to about 5,000μg/min, about 150 μg/min to about 4,000 μg/min or about 200 μg/min toabout 3,500 μg/min); (b) an output rate of muscarinic antagonist of atleast about 2 times, 3 times or 4 times the output rate achievable witha conventional nebulizer (for example, where the muscarinic antagonistis glycopyrrolate, the output rate is at least about 120 μg/min, atleast about 150 μg/min, at least about 200 μg/min or at least about 200μg/min to about 5,000 μg/min); (i) a respirable fraction (RE) ofmuscarinic antagonist of at least about 30%, at least about 35%, atleast about 40%, at least about 45%, at least about 50%, at least about55%, at least about 65% to at least about 75% or at least about 75% toat least about 85% respirable fraction upon administration; (ii) aGeometric Standard. Deviation (GSD) of emitted droplet size distributionof the solution administered with a inhalation device of about (iii)about 1.1 to about 2.1, about 1.2 to about 2.0, about 1.3 to about 1.9,about 1.4 to about 1.8, about 1.5 to about 1.7, about 1.4, about 1.5, orabout 1.6; (iv) or a Mass Median Aerodynamic Diameter (MMAD) of dropletsize of the solution emitted with the inhalation device of about 1 μm toabout 5 μm, about 2 to about 4 μm, about 3 to about 4 μm, or about 3.5to about 4.0 μm.

In accordance with the invention, in some embodiments, a high efficiencynebulizer may be adapted or adaptable to operate in conjunction with aunit dosage form, such as an ampule or vial, which contains a singledose of a muscarinic antagonist composition for the treatment of COPD.The unit dosage form comprises a container that contains an inhalationsolution comprising the muscarinic antagonist, such as glycopyrrolate.The container is adapted to cooperate with the high efficiency nebulizerdevice in such a way as to permit administration of the nominal dose ofthe inhalation solution to a patient. In some embodiments, the highefficiency nebulizer and the unit dosage form are configured so thatthey are useable together, but not with other devices or dosage forms.In some particular embodiments, the unit dosage form is configured suchthat it fits into a keyhole-like structure in the high efficiencynebulizer, but will not operate with other nebulizer devices. In suchembodiments, the high efficiency nebulizer is configured such that itwill accept and properly operate with the unit dosage form containingthe muscarinic antagonist, but not with other dosage forms.

Additional features of a high efficiency nebulizer with perforatedmembranes are disclosed in U.S. Pat. Nos. 6,962,151, 5,152,456,5,261,601, and 5,518,179, each of which is hereby incorporated byreference in its entirety. Other embodiments of the high efficiencynebulizer contain oscillatable membranes. Features of these highefficiency nebulizers are disclosed in U.S. Pat. Nos. 7,252,085;7,059,320; 6,983,747, each of which is hereby incorporated by referencein its entirety.

Commercial high efficiency nebulizers are available from: PARI (Germany)under the trade name eFlow®; Aerogen, Ltd. (Ireland) under the tradenames AeroNeb® Go and AeroNeb® Pro, AeroNeb® Solo, and other nebulizersutilizing the OnQ® nebulizer technology; Respironics (Murrysville,Calif.) under the trade names I-Neb®; Omron (Bannockburn, Ill.) underthe trade name Micro-Air®; Activaero (Germany) under the trade nameAkita®, and AerovectRx (Atlanta, Ga.) under the trade name AerovectRx®.Other high efficiency nebulizers are contemplated within the scope ofthis disclosure; and the recitation of particular high efficiencynebulizers is not intended to exclude other high efficiency nebulizersfrom the scope of the invention.

Conventional Nebulizers

Conventional nebulizers include, for example jet nebulizers orultrasonic nebulizers. Jet nebulizers generally utilize compressors togenerate compressed air, which breaks the liquid medication into smallbreathable droplets, which form an aerosolized (atomized) mist. In someof these embodiments, when the patient breathes in, a valve at the topopens, which then allows air into the apparatus, thereby speeding up themist generation; when the patient breathes out, the top valve closes,thereby slowing down the mist generation while simultaneously permittingthe patient to breathe out through the opening of a mouthpiece flap.

In general, conventional nebulizers are characterized by relatively lowefficiency in delivery of a muscarinic antagonist to the lung. Thus, aconventional nebulizer, such as a jet nebulizer, is characterized by oneor more of the following: (1) about 20% or less calculated respirabledose or measured deposited lung dose as a percentage of the nominal doseof API administered to the patient; (2) a respirable dose delivery rate(RDDR) of less than about 100 μg/min of the muscarinic antagonist, whenglycopyrrolate, administered to the patient; (3) an output rate of lessthan about 100 μg/min of glycopyrrolate administered to the patient; (4)a residual volume of greater than about 10% of the nominal dose of themuscarinic antagonist.

Some conventional nebulizers are disclosed in U.S. Pat. Nos. 6,513,727,6,513,519, 6,176,237, 6,085,741, 6,000,394, 5,957,389, 5,740,966,5,549,102, 5,461,695, 5,458,136, 5,312,046, 5,309,900, 5,280,784, and4,496,086, each of which is hereby incorporated by reference in itsentirety.

Commercial conventional nebulizers are available from: PARI (Germany)under the trade names PART LC Plus®, LC Star®, and PARI-Jet®, A & HProducts, Inc. (Tulsa, Okla.) under the trade name AquaTower®; HudsonRCI (Temecula, Calif.) under the trade name AVA-NEB®; Intersurgical,Inc. (Liverpool, N.Y.) under the trade name Cirrus®; Salter Labs (Arvin,Calif.) under the trade name Salter 8900®; Respironics (Murrysville,Pa.) under the trade name Sidestream®, Bunnell (Salt Lake City, Utah)under the trade name Whisper Jet®; Smiths-Medical Myth Kent, UK) underthe trade name Downdraft®, and DeVilbiss (Somerset, Pa.) under the tradename DeVilbiss®.

Active Ingredient(s)

Muscarinic Antagonists

Acetylcholine released from cholinergic neurons in the peripheral andcentral nervous systems affects many different biological processesthrough interaction with two major classes of acetylcholine receptors:the nicotinic and the muscarinic receptors.

Muscarinic acetylcholine receptors are widely distributed in vertebrateorgans where they mediate many vital functions. Three subtypes ofmuscarinic acetylcholine receptors have been identified as important inthe lung, M1, M2, and M3, each with its unique pharmacologicalproperties and a product of a distinct gene. These three subtypes arealso located in organs other than the lung.

In the lung, M3 muscarinic receptors mediate smooth muscle contraction.Stimulation of M3 muscarinic receptors activate the enzyme phospholipaseC via binding of the stimulatory G protein Gq/11 (Gs), leading toliberation of phosphatidyl inositol-4, 5-bisphosphate, resulting inphosphorylation of contractile proteins and bronchial constriction. M3muscarinic receptors are also found on pulmonary submucosal glands.Stimulation of this population of M3 muscarinic receptors results inmucus secretion. M2 muscarinic receptors make up approximately 50-80% ofthe cholinergic receptor population on airway smooth muscles. Undernormal physiological conditions; M2 muscarinic receptors provide tightcontrol of acetylcholine release from parasympathetic nerves. M1muscarinic receptors are found in the pulmonary parasympathetic gangliawhere they function to enhance neurotransmission.

Muscarinic acetylcholine receptor dysfunction in the lungs has beennoted in a variety of different pathophysiological states. In COPDpatients, inflammatory conditions lead to loss of inhibitory M2 and M3muscarinic acetylcholine autoreceptor function on parasympathetic nervessupplying the pulmonary smooth muscle, causing an increased release ofacetylcholine. This dysfunction in muscarinic receptors results inairway hyperreactivity and hyperresponsiveness.

Muscarinic acetylcholine receptor antagonist agents, or muscarinicantagonists, have the ability to inhibit the action of theneurotransmitter acetylcholine by blocking its interaction withmuscarinic cholinergic receptors in general, and its interaction withspecific muscarinic receptor subtypes in particular. Muscarinicantagonists thereby prevent the effects resulting from the passage ofunnecessary impulses through the parasympathetic nerves mediated byincreased stimulation in patients with dysfunctional receptors,resulting in, among other physiological effects, relaxation of smoothmuscles in the lung.

Aclidinium,((3R-3-{[hydroxydi(thiophen-2-yl)acetyl]oxy}-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanebromide), is a specific long-acting muscarinic receptor antagonist.Aclidinium is in development for use as an anticholinergic agent.Clinically, aclidinium has been tested in a dry powder inhaled format.

In some embodiments of the present invention, the muscarinic antagonistis aclidinium and is administered at a nominal dosage of 100 μg/dose toabout 5 mg/dose, about 50 μg/dose to about 2 mg/dose or about 50 μg/doseto about 1 mg per dose. In other embodiments, aclidinium is given in 100μg, 200 μg, 300 μg, 400 μg, 500 μg, 600 μg, 700 μg, 800 μg, 900 μg, or1,000 μg doses.

The process of making aclidinium is known by a person of ordinary skillin the art. Aclidinium can be made by a number of known methodsincluding those described in U.S. Pat. No. 6,750,226, which isincorporated herein by reference in its entirety, and which sets forthseveral structurally related muscarinic antagonists. Additional examplesof muscarinic antagonists are set forth in U.S. Pat. Nos. 7,312,231 and7,208,501, each of which is incorporated herein by reference in itsentirety.

Trospium(endo-3-[(Hydroxydiphenylacetyl)oxy]spiro[8-azoniabicyclo[3.2.1]ocatane-8,1′-pyrrolidinium]chloride benzilate), is a specific long-acting muscarinic; receptorantagonist. Trospium has been known for many years to be an effectiveanticholinergic agent. Clinically, trospium has been used in severalindications and been delivered by a number of different routes.Currently, trospium is used as a urinary antispasmotic and is sold underthe brand name Sanctura®.

In some embodiments of the present invention, the muscarinic antagonistis trospium and is administered at a nominal dosage of 10 μg/dose toabout 5 mg/dose, about 10 μg/dose to about 2 mg/dose or about 50 μg/doseto about 1 mg per dose. In other embodiments, trospium is given in 10μg, 50 μg, 100 μg, 200 μg, 300 μg, 400 μg, 500 μg, 600 μg, 700 μg, 800μg, 900 μg, or 1,000 μg doses.

The process of making trospium is known by a person of ordinary skill inthe art. Trospium can be made by a number of known methods includingthose described in U.S. Pat. No. 3,480,626, which is incorporated hereinby reference in its entirety.

Glycopyrrolate,3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium, is aspecific long-acting muscarinic receptor antagonist. Glycopyrrolate hasbeen known for many years to be an effective anticholinergic agent.Clinically, glycopyrrolate has been used in several indications and beendelivered by a number of different routes. Currently, glycopyrrolate isapproved for use as an injectable compound to reduce secretions duringanesthesia and also as an oral product for treating gastric ulcers.

In some embodiments of the present invention, the muscarinic antagonistis glycopyrrolate and is administered with a high efficiency nebulizerat a nominal dosage of about 25 μg/dose to about 1 mg/dose, about 25pig/dose to about 0.5 mg/dose, about 25 μg/dose to about 400 μg/dose,about 25 μg/dose to about 300 μg/dose, about 25 μg/dose to about 200μg/dose, about 25 μg/dose to about 150 μg/dose, about 25 μg/dose toabout 125 μg/dose, about 25 μg/dose to about 100 μg/dose 50 μg/dose toabout 1 mg/dose, about 50 μg/dose to about 0.5 mg/dose, about 50 μg/doseto about 300 μg/dose, about 50 μg/dose to about 250 μg/dose, about 50μg/dose to about 200 μg/dose, about 50 μg/dose to about 150 μg/dose,about 50 μg/dose to about 125 μg/dose, about 50 μg/dose to about 100μg/dose, less than about 150 μg/dose, less than about 100 μg/dose, equalto or less than about 80 μg/dose, 100 μg/dose to about 5 mg/dose, about200 μg/dose to about 2 mg/dose or about 250 μg/dose to about 1 mg perdose. In some preferred embodiments, the muscarinic antagonist isglycopyrrolate and is administered with a high efficiency nebulizer at anominal dosage of about 25 μg, about 30 μg, about 35 μg, about 40 μg,about 45 μg, about 50 μg, about 55 μg, about 60 μg, about 65 μg, about70 μg, about 75 μg, about 80 μg, about 85 μg, about 90 μg, about 95 μg,about 100 μg, about 110 μg, about 120 μg, about 125 μg, about 130 μg,about 135 μg, about 140 μg, about 150 μg, about 160 μg, about 170 μg,about 175 μg, about 180 μg, about 190 μg, about 200 μg, about 25 μg toabout 500 μg, about 50 μg to about 500 μg, about 50 μg to about 300 μg,about 50 μg to about 250 μg, about 50 μg to about 200 μg, about 50 μg,about 75 μg, about 100 μg, about 125 μg, about 150 μg, about 175 μg,about 200 μg, about 225 μg, about 250 μg, about 275 μg or about 300 μgof glycopyrrolate per dose, in some preferred embodiments,administration of the nominal dose of glycopyrrolate with a highefficiency nebulizer produces clinically meaningful improvement in lungfunction in a COPD patient at least 24 hours after administration of asingle dose.

The process of making glycopyrrolate is known by a person of ordinaryskill in the art. Glycopyrrolate can be made as follows. First,alpha-phenylcyciopentaneglycolic acid is esterified by refluxing withmethanol in the presence of hydrochloric acid and the resulting ester istransesterified with 1-methyl-3-pyrrolidinol using sodium as a catalyst;the transester is then reacted with methyl bromide to giveglycopyrrolate. U.S. Pat. No. 6,433,003, which describes this process inmore detail, is hereby incorporated by reference in its entirety.

Glycopyrrolate for injectable and oral administration is readilycommercially available. Injectable glycopyrrolate in commercialadministrations are sold by: Baxter Healthcare, Inc. (Deerfield, Ill.)under the trade name Robinul and by Luitpold Pharmaceuticals, Inc.(Shirley, N.Y.) under the generic name glycopyrrolate. Oralglycopyrrolate is commercially available under the generic nameglycopyrrolate from Corepharma, LLC (Middlesex, N.J.) and KaliLaboratories, Inc. (Somerset, N.J.), and is available from ScielePharma, Inc. (Atlanta, Ga.) under the trade names Robinul and RobinulForte.

Tiotropium is another long-acting muscarinic antagonist that may bementioned. In some embodiments, the dose of tiotropium administered witha high efficiency nebulizer will be less than about 15 μg, less thanabout 12 μg, less than about 10 μg or less than about 8 μg. In someembodiments, the dose will be in a range of about 1-10 μg, about 1-9 μg,about 1-8 μg or about 1-5 μg about 1 μg, about 2 μg, about 3 μg, about 4μg, about 5 μg, about 6 μg, about 7 μg, about 8 μg, about 9 μg or about10 μg per dose.

Muscarinic antagonists can be long-acting or short-acting. Long-actingmuscarinic antagonists have a therapeutic effect lasting greater thanabout 6 hours. Short-acting muscarinic antagonists have a duration oftherapeutic effect of less than about 6 hours. Long-acting muscarinicantagonists include, but are not limited to, glycopyrrolate, tiotropium,aclidinium, trospium, QAT370, GSK233705, GS K656398, BEA 2180, or apharmaceutical acceptable derivative, salt, enantiomer, diastereomer, orracemic mixtures thereof.

Short-acting muscarinic antagonists include, but are not limited toipratropium, oxitropium or a pharmaceutical acceptable derivative, salt,enantiomer, diastereomer, or racemic mixtures thereof.

In some embodiments, the muscarinic antagonist is glycopyrrolate,tiotropium, aclidinium, trospium, QAT370, GSK233705, GSK 656398,BEA2180, ipratropium, oxitropium, oxybutynin or a pharmaceuticalacceptable derivative, salt, enantiomer, diastereomer, or apharmaceutical acceptable derivative, salt, enantiomer, diastereomer, orracemic mixture thereof.

In some embodiments, the inhalation solution comprising the muscarinicantagonist(s) further comprises a corticosteroid, such as fluticasone,mometasone, beclomethasone, triamcinolone, fluniolide, ciclesonide, orbudesonide. In some embodiments, the inhalation solution furthercomprises an excipient, including an organic acid, such as citric acid,ascorbic acid or optionally a combination of both, pilocarpine,cevimeline or carboxymethylcellulose, or a mucolytic compound. In someembodiments, the inhalation solution contains muscarinic antagonist(such as glycopyrrolate) a beta 2-adrenoceptor agonist and/or acorticosteroid or non-steroidal anti-inflammatory.

Beta 2-Adrenoceptor Agonists

The stimulation of beta 2-adrenergic receptors stimulate adenylatecyclase, resulting in an increased level of the second messenger cAMPthat in turn leads to decreased intracellular calcium concentration andconsequently smooth muscle relaxation. Stimulation of certain beta2-adrenoceptor receptors in particular causes hydrolysis ofpolyphosphoinositides and mobilization of intracellular calcium whichresults in a variety of calcium mediated responses such as smooth musclecontraction. Consequently, inhibition of this receptor activationprevents the intracellular calcium increase and leads to smooth musclerelaxation.

Beta 2-adrenoceptor agonists can be long-acting or short-acting.Long-acting beta 2-adrenoceptor agonists (LABAs) have a therapeuticeffect lasting greater than about 6 hours. Short-acting beta2-adrenoceptor agonists (SABA s) have a duration of therapeutic effectof less than about 6 hours.

Compounds having beta 2-adrenoceptor agonist activity with a long-actingor short-acting effect have been developed to treat respiratoryconditions. Such compounds include, but are not limited to, albuterol;bambuterol; bitoiterol; broxaterol; carbuterol; clenbuterol; ibuterol;sulfonterol; isoproterenol; trimetoquinol; formoterol; desformoterol;hexoprenaline; ibuterol; indaeaterol; isoetharine; isoprenaline;isoproterenol; levalbuterol; metaproterenol; picumeterol; pirbuterol;procaterol; reproterol; rimiterol; salbutamol, salmeterol; suifonteroi;terbutaline; trimetoquinol; tulobuterol; and TA-2005(8-hydroxy-5-((1R)-1-hydroxy-2-(N-((1R)-2-(4-methoxyphenyl)-1-methylethyl)amino)ethyl)-carbostyril hydrochloride); or a or a pharmaceuticalacceptable derivative, salt, enantiomer, diasteriomer, or racemicmixtures thereof.

Formoterol is a long-acting beta 2-adrenoceptor compound. The process ofmaking formoterol is known by one of skill in the art. Formoterol isderived from adrenaline and is used as a beta 2-adrenoceptor agonist ininhalation therapy of respiratory diseases. Formoterol has beenformulated as a dry powder and administered via devices such as theTurbuhaler® and the Aerolizer®.

Formoterol is also available as a tablet and a dry syrup in certainareas of the world (e.g., Atock®, marketed by Yamanouchi PharmaceuticalCo. Ltd., Japan). Formoterol administrations are also available in otherareas (e.g., Europe and U.S.) for propellant-based metered dose inhalersand dry powder inhalers (e.g., Turbuhaler®, Aerolizer.® and ForadilAerolizer®). None of these administrations are water based solutions.

Commercial administrations of arformoterol tartrate (formoterol) aresold by Sepracor, Inc, (Marlborough, Mass.) under the trade nameBrovana®. Formoterol fumarate is sold by several companies includingAstraZeneca, Inc. (London, England) under the trade name Symbicort®,Novartis International AG (Basel, Switzerland) under the trade namesForadil® and Certihaler®, and Dey, L. P. (Napa, Calif.) under the tradename Perforomist®.

Salmeterol is a long-acting beta 2-adrenoceptor compound. The processfor making salmeterol is known by a person of ordinary skill in the artand is described in U.S. Pat. No. 4,992,474, which is herebyincorporated by reference. Commercial administrations of salmeterol aresold by GlaxoSmithKline, Inc. (Triangle Park, N.C.) under the tradenames Advair® and Serevent®.

Inhalation Solutions

The present invention relates to methods and inhalation systems for theuse of inhalation solutions in an inhalation device for the treatment orprophylaxis of a respiratory condition in a patient, such as COPD,chronic bronchitis, or emphysema. In some embodiments, the methods andinhalation systems comprise administering to the patient a nominal doseof one or more API, for example muscarinic antagonist (optionally incombination with a beta 2-adrenoceptor agonist and/or a corticosteroid)in an aqueous inhalation solution with an inhalation device, e.g. a highefficiency nebulizer, conventional nebulizer, and optionally aconventional inhalation device.

In some embodiments, an aqueous inhalation solution containingglycopyrrolate is administered with a high efficiency nebulizer at aconcentration greater than about 0.5 mg/mL. In some embodiments, anaqueous inhalation solution containing glycopyrrolate is administeredwith a high efficiency nebulizer at a concentration of 0.05 mg/mL toabout 2.0 mg/mL, at least about 0.05 mg/mL, at least about 0.5 mg/mL, atleast about 1.0 mg/mL to about 2.0 mg/mL, at least about 0.25 mg/mL, atleast about 0.5 mg/mL, at least about 1.0 mg/mL, at least about 1.5mg/mL, or at least about 2.0 mg/mL. Without wishing to be bound bytheory, it is believed that the higher concentration of muscarinicantagonist, for example glycopyrrolate, results in saturation and/ortargeting of a greater number of muscarinic receptors with themuscarinic antagonist and/or targeting of the muscarinic receptors withthe muscarinic antagonist for a greater period of time. In someembodiments, it is believed that administration of a muscarinicantagonist, such as glycopyrrolate, at a concentration of at least about100 to about 300 μg/mL will result in greater duration and/or magnitudeof therapeutic effect. Without wishing to be bound by theory, it isbelieved that the higher concentration of muscarinic antagonist, forexample glycopyrrolate, coupled with the improved delivery and/or lungdistribution achievable with a high efficiency nebulizer, results insaturation and/or targeting of a greater number of muscarinic receptorswith the muscarinic antagonist and/or targeting of the muscarinicreceptors with the muscarinic antagonist for a greater period of time.In some embodiments, it is believed that administration of a muscarinicantagonist, such as glycopyrrolate, in a nebulized form having an MMADof less than about 4 μm and a USD of less than about 1.8, wherein theloaded dose has a concentration greater than 0.25 mg/mL, will result ingreater duration and/or magnitude of therapeutic effect. Without wishingto be bound by theory, it is believed that this combination ofcharacteristics results in saturation and/or targeting of a greaternumber of muscarinic receptors with the muscarinic antagonist and/ortargeting of the muscarinic receptors for a greater period of time.

In some embodiments, the methods, devices and systems employ an aqueousinhalation solution containing glycopyrrolate, at an administration ofabout 25 μg/dose to about 1 mg/dose, about 25 μg/dose to about 500μg/dose, about 25 μg/dose to about 400 μg/dose, about 25 μg/dose toabout 250 μg/dose, about 50 μg/dose to about 1 mg/dose, about 50 μg/doseto about 500 μg/dose, about 50 μg/dose to about 400 μg/dose, about 50μg/dose to about 250 μg/dose, about 25 μg/dose to about 5 mg/dose, about200 μg/dose to about 2 mg/dose, or about 250 μg/dose to about 1 mg perdose. In some embodiments, the methods, devices and systems comprise acomposition containing glycopyrrolate in an amount of about 50 μg/doseto about 1 mg/dose, about 50 μg/dose to about 0.5 mg/dose, about 50μg/dose to about 250 μg/dose, about 50 μg/dose to about 150 μg/dose,about 50 μg/dose to about 125 μg/dose, about 50 μg/dose to about 100μg/dose, less than about 150 μg/dose, less than about 100 μg/dose, equalto or less than about 80 μg/dose, 100 μg/dose to about 5 mg/dose, about200 μg/dose to about 2 tug/dose or about 250 μg/dose to about 1 mg perdose.

In some embodiments, the aqueous inhalation solution is administeredwith an inhalation device, e.g. high efficiency nebulizer, at a fillvolume of about 0.1 to about 1.0 mL, e.g. about 0.3 to about 0.7 mL. Insome embodiments, the fill volume is less than about 0.5 mL, at leastabout 0.5 mL, to about 1.5 mL, at least about 0.25 mL or less, at leastabout 0.5 mL to about 1.5 mL, at least about 1.5 mL, or at least about2.0 mL. In some embodiments, the aqueous inhalation solution isadministered with an inhalation device, e.g. high efficiency nebulizer,at a fill volume of at least about 0.25 mL to about 2.0 mL, about 0.5 mLto about 1.5 mL, about 0.5 mL to about 1.0 mL, about 0.5 mL or less,about 1 mL or less, about 1.5 mL or less, or about 2.0 mL or less. Insome embodiments, the aqueous inhalation solution is administered withan inhalation device, e.g. high efficiency nebulizer, which provides fora residual volume of muscarinic antagonist after administration of themuscarinic antagonist of less than about 10%, less than about 5%, orless than about 3% of the nominal dose.

In some embodiments, the aqueous inhalation solution is administered inabout 0.25 to about 10 minutes, about 0.50 to about 8 minutes, less thanabout 8, less than about 7, less than about 6, less than about 5, lessthan about 4, less than about 3, less than about 2, less than about 1.75minutes, or less than about 1.5 minutes. In some embodiments, theaqueous inhalation solution is administered in about 3 minutes or less.

In some embodiments, a muscarinic antagonist is co-administered with abeta 2-adrenoceptor agonist in the aqueous inhalation solution. In someembodiments, the beta 2-adrenoceptor agonist is a long-acting betaagonist (LABA). In some embodiments, the beta 2-adrenoceptor agonist isa short-acting beta agonist (SABA). In some embodiments, the beta2-adrenoceptor agonist is either a SABA or a LAMA.

In some embodiments, the nominal, dose administered with the highefficiency nebulizer is a muscarinic antagonist (optionally incombination with a beta 2-adrenoceptor agonist and/or corticosteroid ornon-steroidal anti-inflammatory) that is substantially free ofpreservative, such as benzyl alcohol. In some embodiments, the nominaldose of muscarinic antagonist (optionally in combination with a beta2-adrenoceptor agonist and/or corticosteroid or non-steroidalanti-inflammatory) is in an inhalation solution that further comprisesat least one excipient or active pharmaceutical ingredient. In someembodiments, the excipient or active ingredient is a member of the groupconsisting of organic acid (such as a low molecular weight organic acidlike citric acid or ascorbic acid), an antioxidant (such as EDTA), anosmolarity adjusting agent (such as a salt like sodium chloride) or a pHbuffer.

In some embodiments, the inhalation solution comprising the muscarinicantagonist(s) further comprises a corticosteroid, such as fluticasone,mometasone, beclomethasone, triamcinolone, fluniolide, ciclesonide, orbudesonide. In some embodiments, the inhalation solution furthercomprises an excipient or an active pharmaceutical ingredient. In someembodiments, the excipient or active pharmaceutical ingredient is anorganic acid (such as citric acid, ascorbic acid, or both), pilocarpine,cevimeline, carboxymethylcellulose, or a mucolytic compound.

Characterization of Inhalation Devices

The efficiency of a particular inhalation device can be measured in manydifferent ways, including an analysis of pharmacokinetic properties,measurement of lung deposition (deposited lung dose), measurement ofrespirable dose delivery rates (RDDR), a determination of output rates,respirable fraction (RF), geometric standard deviation (GSD), massmedian aerodynamic diameter (MMAD), and mass median diameter (MMD) amongothers.

A person skilled in the art is knowledgeable of methods and systems forexamining a particular inhalation device. One such system consists of acomputer and a hollow cylinder in a pump with a connecting piece towhich an inhalation device is to be connected. In the pump there is apiston rod, which extends out of the hollow cylinder. A linear driveunit can be activated in such a manner that one or more breathingpattern will be simulated on the connecting piece of the pump. In orderto be able to carry out the evaluation of the inhalation device, thecomputer is connected in an advantageous configuration with a datatransmission. With the aid of the data transmission, the computer can beconnected with another computer with specific data banks, in order toexchange the data of breathing patterns. In this manner, a breathingpattern library which is as representative as possible can be very,rapidly formed. U.S. Pat. No. 6,106,479 discloses this method forexamining an inhalation device in more detail, and is herebyincorporated by reference in its entirety.

Pharmacokinetic Profile

Pharmacokinetics is concerned with the uptake, distribution, metabolismand excretion of a drug substance. A pharmacokinetic profile comprisesone or more biological measurements designed to measure the absorption,distribution, metabolism and excretion of a drug substance. One way ofvisualizing a pharmacokinetic profile is by means of a blood plasmaconcentration curve, which is a graph depicting mean active ingredientblood plasma concentration on the Y-axis and time (usually in hours) onthe X-axis. Some pharmacokinetic parameters that may be visualized bymeans of a blood plasma concentration curve include:

AUC_((0-t)): The area under the curve from time zero to time of lastmeasurable concentration.

AUC_((0-∞)): The total area under the curve.

C_(max): The maximum plasma concentration in a patient.

T_(max): The time to reach maximum plasma concentration in a patient

T½: The elimination half life.

An enhanced pharmacokinetic profile in a patient can be indicated by anincreased AUC_((0-t)), AUC_((0-∞)), C_(max), T½, or T_(max), or anincreased slope in the plasma concentration curve within the first hourafter treatment. Enhanced levels of a pharmaceutical agent in the bloodplasma of a patient may result in one or more improved symptoms of anairway respiratory condition, e.g. COPD.

In some embodiments, a method or system described herein provides atleast about a two-fold enhancement in pharmacokinetic profile, meaningthat administration of an active pharmaceutical ingredient (“API”—e.g. amuscarinic antagonist, optionally in combination with a beta2-adrenergic agonist) with a high efficiency nebulizer provides at leastabout a two-fold increase in one or more of AUC_(last), AUC_((0-∞)), orC_(max) as compared to the same or lower nominal dose of APIadministered with a conventional nebulizer.

In some embodiments, a method or system described herein provides atleast about a two-fold enhancement in pharmacokinetic profile, meaningthat administration of an active pharmaceutical ingredient (“API”—e.g. amuscarinic antagonist, optionally in combination with a beta2-adrenergic agonist) with a high efficiency nebulizer provides at leastabout a 1.8-fold increase in one or more of AUC_(last), AUC_((0-∞)), orC_(max) as compared to the same or lower nominal dose of APIadministered with a conventional nebulizer.

In some embodiments, a method or system described herein provides atleast about a two-fold enhancement in pharmacokinetic profile, meaningthat administration of an active pharmaceutical ingredient (“API”—e.g. amuscarinic antagonist, optionally in combination with a beta2-adrenergic agonist) with a high efficiency nebulizer provides at leastabout a 1.5-fold increase in one or more of AUC_(last), AUC_((0-∞)), orC_(max) as compared to the same or lower nominal dose of APIadministered with a conventional nebulizer.

In some embodiments, a method or system described herein provides atleast about a two-fold enhancement in pharmacokinetic profile, meaningthat administration of an active pharmaceutical ingredient (“API”—e.g. amuscarinic antagonist, optionally in combination with a beta2-adrenergic agonist) with a high efficiency nebulizer provides acomparable AUC_(last), AUC_((0-∞)), or C_(max) as compared to the sameor lower nominal dose of API administered with a conventional nebulizer.

Enhanced Therapeutic Effect

The assessment of therapeutic effect is known to those skilled in theart, such as pulmonologists trained to recognize the distinctionsbetween various types of respiratory illnesses, including chronicobstructive airway disease (“COPD”) and asthma. Assessment of efficacymay be carried out by various methods known to the person skilled in theart, and may include both objective and subjective (patient-generated)measures of efficacy. Objective measures of efficacy can be obtainedinter aria by spirometry; and subjective measures of efficacy can beobtained for example by employing one or more patient symptomquestionnaires or surveys. In some embodiments, the methods and systemsherein are for treatment of COPD, and thus such embodiments arediscussed in further detail below. It is considered that embodiments ofthe methods and symptoms described herein. (including those employingadministration of muscarinic antagonist, optionally in combination witha beta 2-adrenoceptor agonist and/or a corticosteroid, with a highefficiency nebulizer or at a high concentration) will provide superiorefficacy in treatment of COPD as compared to treatment with conventionalmethods (such as those in which muscarinic antagonist is administeredwith a conventional nebulizer and/or at a lower concentration).

COPD Efficacy Assessment

COPD is a progressive, chronic disease of the airways, characterized bychronic inflammation and destruction of the airways and lung parenchyma,resulting in airflow obstruction. Thus, efficacy in the treatment ofCOPD refers to the ability to restore airflow to the patient. In somecases, especially in older and immune-compromised patients, COPD can befurther characterized by exacerbations—acute, often pathogen- orallergen-induced, degradation of airflow. There are several indicators(endpoints) of efficacy in the treatment of COPD. Some efficacyendpoints that are used in COPD studies are set forth below. It isconsidered that a muscarinic antagonist will demonstrate efficacy in oneor more of these tests. In particular, it is considered that in someembodiments a nominal dose of a muscarinic antagonist administered witha high efficiency nebulizer will out-perform substantially the same orhigher nominal dose of muscarinic antagonist administered with aconventional nebulizer, as determined by one or more of these endpoints.

Pulmonary function tests: Pulmonary function testing by spirometry is auseful way to assess airflow obstruction and, therefore, is a useful wayto assess the efficacy of COPD treatment as well as to compare therelative merits of different COPD treatments—e.g. administration ofdifferent dosages of active pharmaceutical ingredient (“API”),administration of substantially the same dosages of API with differentdelivery devices, or administration of different dosages of API withdifferent delivery devices. Forced expiratory volume in one second(FEV₁) obtained from typical spirometry is commonly used as an efficacyendpoint because FEV₁ is a reflection of the extent of airwayobstruction. Spirometry is also well-standardized, is easy to performand provides consistent, reproducible results across different pulmonaryfunction laboratories. Air-trapping and hyperinflation are commonfeatures in COPD, particularly in emphysema, and are reflected inparameters of lung function testing, such as an elevation in theresidual volume to total lung capacity ratio (RV/TLC). Hyperinflation isbelieved to be responsible, at least in part, for the sense of dyspnea.

Outcome Measures can also be used, alone or preferably in combinationwith one or more objective tests, to determine efficacy of COPD therapy.

Exacerbation: The progressive course of COPD is often aggravated byperiods of exacerbations generally defined as increased symptoms,particularly increasing cough, dyspnea and production of sputum overbaseline that usually requires change in treatment. Exacerbations aremostly caused by bronchial infections and are the most frequent cause ofmedical visits, hospital admissions and death in patients with COPD. Oneof the main objectives of COPD treatment is to reduce the frequency andseverity of exacerbations and the frequency of hospitalizations andduration of hospital stay. The characteristics, including thelimitations, of these tests will be known to those skilled in the art.

Exercise capacity: Reduced capacity for exercise is a typicalconsequence of airflow obstruction in COPD patients, particularlybecause of dynamic hyperinflation occurring during exercise. Exercisetesting provides useful assessment of the degree of lung impairment,prognosis and the effects of treatments. Assessment of exercise capacityby treadmill or cycle ergometry combined with lung volume assessment isin some cases a tool to assess efficacy of a COPD drug. Alternativeassessments of exercise capacity, such as the Six Minute Walk or ShuttleWalk, can also be used in some cases. The characteristics, including thelimitations, of these tests will be known to those skilled in the art.

Symptom Scores: Symptom scores determined by asking patients to evaluatespecific symptoms on a categorical, visual or numerical scale can be asimple way to assess efficacy of a drug based on the patient's ownassessment of health status. Symptom scores can be valuable forassessing efficacy of a drug specifically aimed at relieving a symptom.In clinical programs aimed at other aspects of COPD, patient-reportedsymptom scores can be useful in assessing secondary effects of thetherapy and may provide important additional evidence of efficacy. Thecharacteristics, including the limitations, of these tests will be knownto those skilled in the art.

Activity Scales: Activity scales provide an assessment of the patient'sseverity of breathlessness and how activities of daily living influencethe patient's breathlessness. Activity scales such as the MedicalResearch Council dyspnea score, the Borg Scale, and the Mahler BaselineDyspnea Index/Transitional Dyspnea Index, can be used in some cases assupportive evidence of efficacy. These scales are relatively simple toadminister. The characteristics, including the limitations, of thesetests will be known to those skilled in the art.

Health-related, quality-of-life instruments: Health-related quality oflife measurement provides a standardized assessment of the impact of thedisease on patients' daily lives, activity and well-being.Health-related quality-of-life instruments, such as the St. George'sRespiratory Questionnaire and the Chronic Respiratory Questionnaire, aredesigned to systematically assess many different aspects of the effectof COPD on a patient's life. These instruments can be used to assessefficacy of a drug. These instruments are multidimensional and assessvarious effects of the disease on a patient's life and health status.The characteristics, including the limitations, of these tests will beknown to those skilled in the art.

Further information regarding testing drugs for efficacy in thetreatment of COPD can be found in the United States Food and DrugAdministration's guidance document entitled: “Guidance for Industry:Chronic Obstructive Pulmonary Disease: Developing Drugs for Treatment,”November, 2007, which is available fromwww.fda.gov/cder/guidance/index.htm.

A muscarinic antagonist is said to have a therapeutic effect in thetreatment of COPD (at a relevant time point) when it causes an increasein one or more measures of pulmonary function to a predeterminedpercentage above baseline. In some embodiments, the predeterminedpercentage above baseline is about 5%, about 10%, about 15%, about 20%,or about 25%. In some specific embodiments, a muscarinic antagonist willbe considered to have a therapeutic effect when it raises one or more ofthe above-mentioned spirometry measurements (e.g. FEV₁) at least about15% above baseline. In general, an improvement in pulmonary function(e.g. FEV₁) of 100 mL or 10% above baseline is considered clinicallyrelevant; and an improvement in pulmonary function above baseline of 100mL or 10% above baseline at 24 hours post dosing is consideredclinically relevant for a QD (1× daily dosing) drug.

Spirometry is the measurement of respiration, which is generallyconducted by a physician with the aid of a spirometer. Spirometersmeasure inspired and expired airflow for the purpose of assessingpulmonary ventilatory function. Spirometry is the most common pulmonaryfunction test measuring lung function. Typical spirometers displayvolume-time curves (showing volume on the Y-axis and time, usually inseconds, on the X-axis) and optionally a flow-volume curves (showingrate of flow on the Y-axis and the total volume inspired/expired on theX-axis). U.S. Pat. No. 7,291,115 discloses a spirometer and method tomeasure the ventilatory function by spirometry, and is herebyincorporated by reference in its entirety. Methods of using a spirometerare familiar to those skill in the art.

Relevant parameters measured by spirometers include:

-   -   FEV1 (or FEV₁): Forced Expiratory Volume in 1 Second, which is        the maximum volume of air exhaled during the first second of        maximum effort from a maximum inhalation. It is expressed in        units of volume (e.g. liters (L)), especially as volume change        from baseline or placebo, and/or in percentage change in FEV₁        from baseline or placebo. It becomes altered in cases of        bronchial obstruction and it is fundamental for diagnosing and        monitoring obstructive diseases, e.g. COPD.    -   Change in FEV₁: Change in FEV₁ may be calculated as the        difference between the FEV₁ value measured after dosing and the        FEV₁ measured immediately prior to dosing. Change in FEV₁ may        also be measured in reference to a placebo. These values may be        expressed in absolute terms or in terms of percent change from        baseline or placebo.    -   FEV₁AUC: This is the area between the FEV1 measurements vs. time        curve (relative to baseline and/or placebo) over a time course.        In some embodiments, the time course is a predetermined period,        such as 12 hr., 18 hr., 24 hr., 30 hr., or 36 hr. FEV₁AUC (e.g.        relative to baseline and/or placebo) may be measured from one        time point to another. Some clinically relevant time courses        include 0-12 hr, 0-24 hr, 12-24 hr after dose administration. In        the context of 24 hour efficacy for QD dosing, the FEV₁AUC(12-24        hr) (baseline- and/or placebo-adjusted FEV₁ area under the curve        (AUC) from 12 to 24 hours after administration of the muscarinic        antagonist to the patient) is particularly, relevant. In some        embodiments, an FEV₁AUC(12-24 hr) of at least 0.5 L·hr for        inhaled glycopyrrolate is required to achieve prolonged duration        of bronchodilation over 24 hours. In some embodiments, an        FEV₁AUC(12-24 hr) of greater than 40% of the FEV₁AUC(0-12 hr)        for inhaled glycopyrrolate is required to achieve prolonged        duration of bronchodilation over 24 hours.    -   Mean FEV₁: This is the mean FEV₁ between two time points,        calculated by dividing the FEV₁AUC_(t1-t2) (wherein t₁ is the        starting time and t₂ is the ending time for the relevant time        course) by the difference between t₂ and t₁. Some clinically        relevant time courses for Mean FEV₁ include 0-12 hr, 0-24 hr,        12-24 hr, after dose administration. In the context of 24 hour        efficacy for QD dosing, the Mean FEV₁ (12-24) (placebo-adjusted        Mean FEV₁ from 12 to 24 hours after the muscarinic antagonist to        the patient) is particularly relevant.    -   Trough FEV₁: This is the FEV₁ value measured just prior to        administration of the drug (e.g. just prior to the next        administration of the drug). In some cases, the trough FEV₁ is        obtained in the morning, just prior to administration of the        drug. In some embodiments, the change in trough FEV₁ is the        difference between the trough FEV₁ for the drug and the trough        FEV₁ for a placebo, after a period of time. In general, for a        once daily (QD) bronchodilator drug, trough FEV₁ (at 24 hours        post-dosing and, prior to administration of the next dose) is        considered the clinically relevant endpoint. In some        embodiments, the change in the trough. FEV₁ is measured over a        predetermined time course, such as 1 wk, 2 wk, 4 wk or 12 wk.    -   FVC: Forced Vital Capacity, which is the maximal volume of air        exhaled with maximal effort from a position of maximal        inhalation. It is expressed in liters and in percentage of a        patient's reference value from baseline,    -   FEV₁/FVC: The quotient of FEV₁ and PVC.    -   FEF: Peak Expiratory Flow, which is the highest expiratory flow        achieved with maximal effort from a position of maximal        inspiration. This is essentially the speed of the air moving out        of the lungs of a patient at the beginning of expiration. It is        expressed in liters/second or in liters/minute.    -   FEF₂₅₋₇₅: Forced Expiratory Flow from 25% to 75% on the        flow-volume curve, which is the average flow (or speed) of air        coming out of the lung during the middle portion of expiration.    -   FEF₂₅₋₅₀: Forced Expiratory Flow from 25% to 50% on the        flow-volume curve, which is another measure of the average flow        (or speed) of air coming out of the lung during the initial        portion of expiration.    -   FIF₂₅₋₇₅: Forced Inspiratory Flow from 25% to 75% on the        flow-volume curve, which is the average flow (or speed) of air        entering the lung during the middle portion of inspiration.    -   FIF₂₅₋₅₀: Forced Inspiratory Flow from 25% to 50% on the        flow-volume curve, which is another measure of the average flow        (or speed) of air entering the lung during the initial portion        of inspiration.

An enhanced therapeutic effect can include an increased magnitude oftherapeutic effect, an enhanced duration of therapeutic effect, anenhanced time to onset of therapeutic effect, a shorter time to maximumtherapeutic effect or a greater magnitude of therapeutic effect. In someembodiments described herein, an enhanced therapeutic effect relates tothe increased ability of a pharmaceutical agent to relieve the symptomsof an airway respiratory disorder, e.g. COPD. Thus, an enhancedtherapeutic effect may be determined by comparing values of change inFEV₁ (i.e. change in FEV₁ from baseline or compared to a placebo). %change in FEV₁ (i.e. percent change in FEV₁ from baseline or compared toplacebo), FEV₁ AUC, trough FEV₁, FEV₁/FVC, PEE, FEF₂₅₋₇₅, FEF₂₅₋₅₀,FIF₂₅₋₇₅, FIF₂₅₋₅₀ obtained from a patient or patient population in onetherapeutic milieu versus another anther therapeutic milieu. Forexample, an enhanced therapeutic effect may be determined by comparingFEV₁ values for a patient or patient population treated with amuscarinic antagonist administered with a high efficiency nebulizeragainst the same drug administered with a conventional nebulizer. Inanother example, an enhanced therapeutic effect may be determined bycomparing FEV₁ values for a patient or patient population treated with amuscarinic antagonist administered at a high concentration against thesame drug administered at a low concentration. In some cases, anenhanced therapeutic effect may be determined by comparing FEV₁ valuesfor a patient or patient population treated with a muscarinic antagonistadministered with a high efficiency nebulizer against a muscarinicantagonist alone administered with a conventional nebulizer. In anotherexample, an enhanced therapeutic effect may be determined by comparingFEV₁ values for a patient or patient population treated with amuscarinic antagonist administered at a high concentration against amuscarinic antagonist alone administered at a low concentration. In someembodiments, the enhanced therapeutic effect is an increased magnitudeof therapeutic effect. In some embodiments, the increased magnitude oftherapeutic effect is an increase in the peak FEV₁ obtained with a highefficiency nebulizer versus the peak FEV₁ obtained with a conventionalnebulizer. In some embodiments, the peak FEV₁ obtained with a highefficiency nebulizer is at least about 10%, 15%, 20%, or 30% above thatobtained with a conventional nebulizer. In some embodiments, the peakFEV₁ obtained with a high efficiency nebulizer is at least about 25 mL,50 mL, or 100 mL above that obtained with a conventional nebulizer. Insome embodiments, the increased magnitude of therapeutic effect is anincrease in the mean FEV₁ obtained with a high efficiency nebulizerversus the mean FEV₁ obtained with a conventional nebulizer. In someembodiments, the mean FEV₁ obtained with a high efficiency nebulizer isat least about 5%, 10%, or 15% above that obtained with a conventionalnebulizer. In some embodiments, the mean FEV₁ obtained with a highefficiency nebulizer is at least about 50 mL, 100 mL, or 150 mL abovethat obtained with a conventional nebulizer. In some embodiments, theincreased magnitude of therapeutic effect is an increase in the AUC forthe FEV₁ versus time curve obtained with a high efficiency nebulizerversus the AUC for the FEV₁ versus time curve obtained with aconventional nebulizer. In some embodiments, the increase in AUC of theFEV₁ versus time curve obtained with a high efficiency nebulizer is atleast about 50%, 75% or 100% above that obtained with a conventionalnebulizer.

In some embodiments, the method or system (e.g. muscarinic antagonist,optionally in combination with a beta 2-adrenergic agonist, administeredat a high concentration and/or with a high efficiency nebulizer)provides an enhanced duration of therapeutic effect, as determined bythe amount of time that a spirometric parameter (e.g. FEV₁, trough FEV₁)is above a predetermined threshold after therapy is administered. Insome embodiments, the predetermined threshold is at least about 5% abovebaseline, at least about 10% above baseline, at least about 15% abovebaseline, at least about 20% above baseline, at least about 25% abovebaseline. In some specific embodiments, the threshold is about 15% abovebaseline. In some specific embodiments, the threshold is about 10% abovebaseline. In some embodiments, the threshold is 50 mL, 100 mL, 150 mL ormore than about 150 mL above baseline. In some specific embodiments, thethreshold is about 100 mL above baseline. Baseline can be determined byeither a one-time reference to the spirometric parameter (e.g, FEV₁)immediately prior to administration of API, or by reference to thespirometric parameter level at several time periods during the studyfollowing administration of placebo to a predetermined set of patients.In some embodiments, baseline is determined based on the level ofspirometric parameter (e.g. FEV₁) immediately prior to administration tothe patient of muscarinic antagonist administered at a highconcentration and/or with a high efficiency nebulizer. In someembodiments, baseline is determined by reference to the level ofspirometric parameter (e.g. FEV₁) at several time periods (e.g., 12hours, 24 hours) during evaluation of certain patients following placeboadministration, with the simultaneous evaluation of other patientsadministered a muscarinic antagonist administered at a highconcentration and/or with a high efficiency nebulizer.

In some embodiments, a duration of therapeutic effect is the periodduring which FEV₁ is at least about 5% above baseline, at least about10% above baseline, at least about 15% above baseline, at least about20% above baseline, at least about 25% above baseline. In some specificembodiments, the duration of therapeutic effect is the amount of timethat the FEV₁ is at least 15% above baseline. In some specificembodiments, the duration of therapeutic effect is the amount of timethat the FEN) is at least 10% above baseline. In some specificembodiments, the duration of therapeutic effect is the amount of timethat the FEV₁ is at least 50 mL, 100 mL, or 150 mL above baseline. Insome embodiments, a duration of therapeutic effect is the period duringwhich FEV₁/FVC is at least about 5% above baseline, at least about 10%above baseline, at least about 15% above baseline, at least about 20%above baseline, at least about 25% above baseline. In some embodiments,the duration of therapeutic effect is the amount of time that theFEV₁/FVC is at least 15% above baseline. In some embodiments, a durationof therapeutic effect is the period during which PEF is at least about5% above baseline, at least about 10% above baseline, at least about 15%above baseline, at least about 20% above baseline, at least about 25%above baseline. In some embodiments, the duration of therapeutic effectis the amount of time that the PEF is at least 15% above baseline. Insome embodiments, a duration of therapeutic effect is the period duringwhich FEF₂₅₋₇₅ is at least about 5% above baseline, at least about 10%above baseline, at least about 15% above baseline, at least about 20%above baseline, at least about 25% above baseline. In some embodiments,the duration of therapeutic effect is the amount of time that theFEF₂₅₋₇₅ is at least 15% above baseline. In some embodiments, a durationof therapeutic effect is the period during which FEF₂₅₋₅₀ is at leastabout 5% above baseline, at least about 10% above baseline, at leastabout 15% above baseline, at least about 20% above baseline, at leastabout 25% above baseline. In some embodiments, the duration oftherapeutic effect is the amount of time that the FEF₂₅₋₅₀ is at least15% above baseline. In some embodiments, a duration of therapeuticeffect is the period during which FIF₂₅₋₇₅ is at least about 5% abovebaseline, at least about 10% above baseline, at least about 15% abovebaseline, at least about 20% above baseline, at least about 25% abovebaseline. In some embodiments, the duration of therapeutic effect is theamount of time that the FIF₂₅₋₇₅ is at least 15% above baseline. In someembodiments, a duration of therapeutic effect is the period during whichFIF₂₅₋₅₀ is at least about 5% above baseline, at least about 10% abovebaseline, at least about 15% above baseline, at least about 20% abovebaseline, at least about 25% above baseline. In some embodiments, theduration of therapeutic effect is the amount of time that the FIF₂₅₋₅₀is at least 15% above baseline.

A significantly greater, or greater, duration of therapeutic effect,indicates that the method or system (e.g. a high efficiencynebulizer-administered muscarinic antagonist) provides an increasedperiod of time the spirometric parameter is above a predeterminedthreshold of about 5% above baseline, about 10% above baseline, about15% above baseline, about 20% above baseline, about 25% above baseline,especially about 15% above baseline, for one or more of the spirometricparameters compared to the same spirometric parameter obtained withsubstantially the same nominal dose of drug administered with adifferent inhalation device, e.g. a conventional nebulizer. In someembodiments, the threshold for the spirometric parameter (e.g. FEV₁, ortrough FEV₁) is 50 mL, 100 mL, 150 mL or more than about 150 mL abovebaseline. In some specific embodiments, the threshold is about 100 mLabove baseline.

“About the same” duration of therapeutic effect means that the method orsystem (e.g. a high efficiency nebulizer-administered muscarinicantagonist, optionally in combination with a beta 2-adrenergic agonist)provides substantially the same period of time that the spirometricparameter is above a predetermined threshold of about 5% above baseline,about 10% above baseline, about 15% above baseline, about 20% abovebaseline, about 25% above baseline, or especially about 15% abovebaseline, for one or more of the above spirometric parameters comparedto the same spirometric parameter obtained with a substantially greaternominal dose of the muscarinic antagonist administered with a differentinhalation device, e.g. conventional nebulizer (referenceadministration).

In some embodiments, an inhalation solution described herein (e.g. amuscarinic antagonist inhalation solution administered with a highefficiency nebulizer and/or at a high concentration) provides a durationof therapeutic effect of at least about 12 hr, about 12 hr to about 24hr, about 18 hr to about 24 hr, about 20 hr to about 24 hr, or at leastabout 24 hr, in some embodiments.

A time to onset of therapeutic effect is the time for the spirometricparameter to reach a predetermined threshold of about 5% above baseline,about 10% above baseline, about 15% above baseline, about 20% abovebaseline, or about 25% above baseline, especially about 15% abovebaseline for one or more of the spirometric parameters of a muscarinicantagonist administered with an inhalation device. An enhanced time toonset of therapeutic effect relates to the increased ability of apharmaceutical agent to relieve the symptoms of an airway respiratorydisorder, e.g. COPD. The enhanced time to onset of therapeutic effectmay be a measure of the FEV₁, FEV₁/FVC, PEF, FEF₂₅₋₇₅, FEF₂₅₋₅₀,FIF₂₅₋₇₅. FIF₂₅₋₅₀ levels.

A significantly shorter, or shorter, time to onset of therapeuticeffect, in some embodiments, means that the method or system (amuscarinic antagonist inhalation solution administered with a highefficiency nebulizer and/or at a high concentration) provides for ashortened period of time for one or more spirometric parameters (e.g,FIND to reach a predetermined threshold of about 5% above baseline,about 10% above baseline, about 15% above baseline, about 20% abovebaseline, or about 25% above baseline, especially about 15% abovebaseline, for one or more of the spirometric parameters compared to thesame spirometric parameter(s) obtained with substantially the samenominal dose of the drug solution administered with a differentinhalation device, e.g. a conventional nebulizer and/or at a lowerconcentration. In other embodiments, “about the same” time to onset oftherapeutic effect means the method or system (e.g. administration of amuscarinic antagonist with a high efficiency nebulizer and/or at a highconcentration) provides for substantially the same period of time forthe spirometric parameter to reach a predetermined threshold of about 5%above baseline, about 10% above baseline, about 15% above baseline, orabout 20% above baseline for one or more of the spirometric parameterscompared to the same spirometric parameter obtained with a substantiallygreater nominal of the dose the drug solution administered with adifferent inhalation device, e.g. a conventional nebulizer.

An inhalation solution that provides an onset of therapeutic effect ofless than about 30 minutes, less than about 25 minutes, less than about20 minutes, less than about 15 minutes, or less than about 10 minutes,in some embodiments, refers to an amount of time for the spirometricparameter to reach a predetermined threshold of about 5% above baseline,about 10% above baseline, about 15% above baseline, or about 20% abovebaseline.

In some embodiments, the methods or systems are provided for thetreatment of acute exacerbations of chronic obstructive pulmonarydisease (AECOPD), chronic bronchitis, and/or emphysema in a patient,comprising administering to the patient a nominal dose of a muscarinicantagonist, optionally in combination with a long-acting or short-actingbeta 2 agonist, with a high efficiency nebulizer to provide a rapidonset of therapeutic effect and a long duration of therapeutic effect.In some embodiments, the rapid onset of therapeutic effect is less thanabout 30 minutes, less than about 25 minutes, less than about 20minutes, less than about 15 minutes or less than about 10 minutes. Insome embodiments, the long duration of therapeutic effect is at leastabout 12 hr to about 24 hr, about 18 hr to about 24 hr, about 20 hr toabout 24 hr or at least about 24 hr.

A time to maximum therapeutic effect means the amount of time for apreselected spirometric parameter to reach its peak level. In someembodiments, an enhanced time to maximum therapeutic effect means thatadministration of a muscarinic antagonist with a high efficiencynebulizer, at a high concentration or both, results in a faster time tomaximum therapeutic effect than would a dose of the muscarinicantagonist administered with a conventional nebulizer or at a lowerconcentration. The parameters used to determine an enhanced time tomaximum therapeutic effect may be one or more of FEV₁, FEV₁/FVC, PEF,FEF₂₅₋₇₅, FEF₂₅₋₅₀, FIF₂₅₋₇₅, or FIF₂₅₋₅₀.

Reduction in Adverse Side Effects

Conventional CORD therapy employing a muscarinic antagonist with aconventional nebulizer often results in deposition of pharmaceuticallyactive ingredient in sections distinct from the lung, e.g., mouth,throat, stomach, and/or esophagus. This results in antagonism ofmuscarinic receptors on peripheral systems other than the lung, forexample in salivary glands, stomach, heart, and/or CNS and elsewhere.Therefore the tolerated doses of systemically active muscarinicantagonists, such as glycopyrrolate, are limited by side-effects suchas, but not limited to, xerostomia (dry mouth), urinary hesitancy andretention, blurred vision, tachycardia, dizziness, insomnia, impotence,mental confusion, excitement, headache, anxiety, hypotension and/orpalpitations.

In the present invention, the bronchodilation and other beneficialactions of a muscarinic antagonist are produced by an inhaled agentproviding for a high therapeutic index for activity in the lung, i.e.lung deposition, compared with deposition of muscarinic antagonist innon-pulmonary regions, i.e. periphery compartments, mouth and pharynx.The present invention further provides for an inhalable muscarinicantagonist with low bioavailability in areas within a patient other thanthe lung (e.g. systemic bioavailability, local oropharyngeal or gastricregions), resulting in a decreased incidence and/or severity of systemicand/or local toxicity and/or side effects. A practitioner of ordinaryskill can quantify a reduction in adverse side effects by measuring theincidence and/or severity of systemic and/or local toxicity and/or sideeffects in a given patient or patient population.

A reduced, or decreased, incidence or severity of systemic and/or localtoxicity and/or side effects means that the method or system (e.g.muscarinic antagonist, optionally in combination with a beta2-adrenoceptor agonist, administered with a high efficiency nebulizerand/or at a high concentration) provides a decreased incidence and/orseverity of systemic and/or local toxicity and/or side effects (forexample dry mouth) in a given patient or patient population compared toa given reference therapy. In some embodiments, the reference therapy isadministration of a muscarinic antagonist with a conventional nebulizer.Some embodiments provide a method for the treatment of COPD in apatient, comprising administering to the patient a nominal dose ofmuscarinic antagonist which, when administered with a high efficiencynebulizer, provides a calculated respirable dose of a muscarinicantagonist with a high efficiency nebulizer, wherein the calculatedrespirable dose of the muscarinic antagonist administered with the highefficiency nebulizer demonstrates a decreased incidence and/or severityof systemic and/or local toxicity and/or side effects in the patient ascompared to a nominal dose that achieves substantially the samecalculated respirable dose of the muscarinic antagonist administeredwith a conventional nebulizer. Some embodiments provide a method for thetreatment of COPD in a patient, comprising administering to the patienta nominal dose of muscarinic antagonist which, when administered with ahigh efficiency nebulizer, provides a deposited lung dose of amuscarinic antagonist with a high efficiency nebulizer, wherein thedeposited lung dose of the muscarinic antagonist administered with thehigh efficiency nebulizer demonstrates a decreased incidence and/orseverity of systemic and/or local toxicity and/or side effects in thepatient as compared to a nominal dose that achieves substantially thesame deposited lung dose of the muscarinic antagonist administered witha conventional nebulizer. Some embodiments provide a system forperforming the foregoing methods.

In some embodiments, the method or system (e.g. administration of amuscarinic antagonist with a high efficiency nebulizer and/or at a highconcentration) provides a method and/or inhalation system foradministration of a muscarinic antagonist in a volume of about 0.5 mL orless, 1 mL or less, 1.5 mL or less, or 2.0 mL or less and wherein themuscarinic antagonist demonstrates less incidence and/or severity ofsystemic and/or local toxicity and/or side effects (for example drymouth) in the patient as compared to substantially the same nominal doseof the muscarinic antagonist administered in a substantially highervolume of solution.

In some embodiments, the method or system (e.g. muscarinic antagonistwith a high efficiency nebulizer and/or at a high concentration)provides for methods and inhalation systems for reducing at least oneside effect of the muscarinic antagonist and providing a duration oftherapeutic effect of at least about 12 hr, about 12 hr to about 24 hr,about 18 hr to about 24 hr, about 20 hr to about 24 hr, or at leastabout 24 hours. In some embodiments, the method or system (e.g.administration of a muscarinic antagonist with a high efficiencynebulizer and/or at a high concentration) provides for co-administrationof other drugs and optionally excipients, for example an organic acid,such as ascorbic acid, citric acid or a mixture of both, pilocarpine,cevimeline or carboxymethylcellulose, or a mucolytic compound.

Enhanced. Lung Deposition

Muscarinic receptors and beta 2-adrenoceptors are widely distributedthroughout the body. The ability to apply these active pharmaceuticalagents (APIs) locally to the respiratory tract with sufficient lungdeposition is particularly advantageous, as it would allow foradministration of lower doses of the drug fostering increased patientcompliance

The principle advantage of administration of a nebulized API solutionwith a high efficiency nebulizer over other methods of pulmonarydelivery of APIs is that the methods and systems described herein offermore efficient delivery of higher doses of API compared to conventionalinhalation methods and systems, resulting in greater efficacy and areduced incidence and optionally a severity of side effects in thepatient. A more efficient delivery of API is evidenced by directdelivery and deposition of an API to the site of action, i.e. the lung(as used herein, “lung” refers to either or both the right and left lungorgans). It can be assumed that substantially all of an API delivered atthe receptor site in the lungs will be absorbed into the blood plasma ofthe patient. In embodiments of the invention, the API is a muscarinicantagonist (optionally in combination with a beta 2-adrenoceptoragonist), such as glycopyrronium bromide (glycopyrrolate).

The deposited dose may be expressed in terms of lung deposition. A lungdeposition of 30% means 30% of the active ingredient in the inhalationdevice just prior to administration is deposited in the lung. Likewise,a lung deposition of 60% means 60% of the active ingredient in theinhalation device just prior to administration is deposited in the lung,and so forth. Lung deposition (deposited lung dose) can be determinedusing methods of scintigraphy or deconvolution. In some embodiments, thepresent invention provides for methods and inhalation systems for thetreatment or prophylaxis of a respiratory condition in a patient,comprising administering to the patient a nominal dose of a muscarinicantagonist solution with a high efficiency nebulizer whereinadministration of the muscarinic antagonist with the inhalation deviceprovides lung deposition (deposited lung dose) of the muscarinicantagonist of at least about 30%, at least about 35%, at least about40%, at least about 45%, at least about 50%, at least about 55%, atleast about 60%, about 30% to about 60%, about 30% to about 55%, about30% to about 50%, about 30% to about 40%, about 30% to about 90%, about40% to about 80%, about 50% to about 60%, or about 60% to about 70%based on the nominal dose of the muscarinic antagonist. In someembodiments, the present invention provides for methods and inhalationsystems for the treatment or prophylaxis of a respiratory condition in apatient, comprising administering to the patient a nominal dose of amuscarinic antagonist in an aqueous inhalation solution with aninhalation device wherein administration of the muscarinic antagonistwith the inhalation device provides lung deposition (deposited lungdose) of the muscarinic antagonist of at least about 15%, at least about20%, at least about 25%, at least about 30%, at least about 35%, atleast about 40%, at least about 45%, at least about 50%, at least about55%, at least about 60%, about 20% to about 40%, about 25% to about 35%,about 25% to about 30%, about 35% to about 90%, about 40% to about 80%,about 50% to about 60%, or about 60% to about 70% based on the nominaldose of the muscarinic antagonist.

Aerosol particle/droplet size is one of the most important factorsdetermining the deposition of aerosol drugs in the airways. The portionof an aerosol that has the highest probability of bypassing the upperairway and depositing in the lung measure between 1 and 5 μm. Particleslarger than this are generally deposited in the oropharyngeal region andare swallowed, while sub-micron particles do not carry much drug and maybe exhaled before deposition takes place or are absorbed systemically.Smaller particles tend to deposit more peripherally in the lung thancoarser particles, which may lead to a different clinical response.Consequently, differences in particle size of the aerosol emitted frominhalation devices may account for some of the variability intherapeutic efficacy and safety. Measurement of particle size,therefore, has an important role in guiding product development and inquality control of the marketed product.

The distribution of aerosol particle/droplet size can be expressed interms of either or both of: The Mass Median Aerodynamic Diameter (MMAD)and the Geometric Standard Deviation (GSD), wherein the MMAD is thedroplet size at which half of the mass of the aerosol is contained insmaller droplets and half in larger droplets and the GSD is thegeometric standard deviation of the particle population. While MMAD ismost often determined by a cascade impactor apparatus, the mass mediandiameter (MMD) is most often measured by laser diffraction and can beused as a surrogate for the MMAD value.

The Fine Particle Fraction (FPF), which is the fraction of particles(which may be expressed as a percentage) that are <5 μm in diameter.

These measures have been used for comparisons of the in vitroperformance of different inhaler device and drug combinations. Ingeneral, the higher the fine particle fraction; the higher theproportion of the emitted dose that is likely to reach the lung.

There are two main methods used to measure aerosol deposition in thelungs. First, γ-scintigraphy is performed by radiolabeling the drug witha substance like 99m-technetium, and scanning the subject afterinhalation of the drug. This technique has the advantage of being ableto quantify the proportion of aerosol inhaled by the patient, as well asregional distribution in the upper airway and lungs. Second, since mostof the drug deposited in the lower airways will be absorbed into thebloodstream, pharmacokinetic techniques are used to measure lungdeposition (deposited lung dose). This technique can assess the totalamount of drug that interacts with the airway epithelium and is absorbedsystemically, but will miss the small portion that may be expectoratedor swallowed after mucociliary clearance, and cannot tell us aboutregional distribution. Therefore, γ-scintigraphy and pharmacokineticstudies are in many cases considered complementary.

The relationship between pulmonary deposition of inhaled β2-agonists andtherapeutic effect is now well-established, since the immediate effectsof these agents on the airways are relatively easy to measure. As thepulmonary dose-response curve for the β2-agonists is sigmoidal (i.e. aninitial slope followed by a plateau), increasing the dose deposited inthe lung will elicit an increased therapeutic effect only if the initialdose was on the rising slope of the dose-response curve.

Lung deposition of a particular drug is influenced by the mass of drugcontained in the nebulized droplets administered to a patient with aparticular Mass Median Aerodynamic Diameter (MMAD) and GeometricStandard Deviation (GSD). In general, there is an inverse relationshipbetween the average MMAD and GSD of a particular nebulizer's emitteddroplets and deposition of the droplets in a patient's lung. A smallerMMAD results in an increased likelihood of lung deposition in a patient.When the MMAD is in the range of about 3.0-4.5 μm, a narrower GSDresults in a higher degree of lung deposition, since a higher percentageof particles will be under 5 μm in diameter. It is believed that, ingeneral, aerosol particles greater than ˜10 μm in aerodynamic diameterdeposit primarily in the oropharynx and are swallowed rather thanreaching the lungs. Because of the plausible link between MMAD and GSDvalues and eventual deposition site within the respiratory tract,smaller MMAD and GSD values may affect both the safety (by reducingnon-pulmonary deposition and possibly thereby, reducing local andpotentially systemic effects) and the efficacy (by increasing the amountof drug actually deposited in the lungs) of drug products administeredwith such high efficiency inhalation devices. Cascade impaction andlaser-diffraction provides for an in vitro method of determining MMAD(or MMD) and GSD data, which can then be plotted onto what usuallyresults in a log-normal shaped curve (depicting mass distribution % onthe Y-axis and droplet diameter on the X-axis). Laser-diffractionmethods are well-known to one of ordinary skill in the art. In additionto laser-diffraction methods, in vitro data for MMAD and GSD can also bemeasured using cascade impaction or time-of-flight analytical methods,both of which are known to one of ordinary skill in the art.

Geometric Standard Deviation (GSD) is a dimensionless measure ofdispersion from a geometric mean, such as the MMAD. In general, thesmaller the GSD for a particular particle size distribution, thenarrower the distribution curve. In some embodiments, administration ofthe muscarinic antagonist with the high efficiency nebulizer provides aGSD of emitted droplet size distribution of the solution administeredwith a high efficiency nebulizer of about 1.1 to about 2.1, about 1.2 toabout 2.0, about 1.3 to about 1.9, less than about 2, at least about 1.4to about 1.8, at least about 1.5 to about 1.7, about 1.4, about 1.5, orabout 1.6. In some embodiments, administration of API with a highefficiency nebulizer provides a Mass Median Aerodynamic Diameter (MMAD)of droplet size of the solution emitted with the high efficiencynebulizer of about 1 μm to about 5 μm, about 2 to about 4 μm, about 3 toabout 4 μm, or about 3.5 to about 4.5 μm.

Respirable Fraction (RF), Emitted Dose (ED) or Delivered Dose (DD),Respirable Dose (RD), and the Respirable Dose Delivery Rate (RDDR) arein vitro-derived (calculated) parameters that provide technicaldimensions for the efficiency of a nebulizer inhalation device. RF,which is measured with a cascade impactor or laser diffractionapparatus, is a generally accepted estimate within the medical communityof the fraction, which may be expressed as a percentage, of drug that isavailable for lung deposition. Droplets of less than 5.0 μm in diameterare considered to penetrate to the lung and can be defined as “RF<5 μm”(i.e. fine particle fraction (FPF)). In some embodiments, administrationof the muscarinic antagonist with a high efficiency nebulizer provides arespirable fraction (RE) of API of at least about 60%, at least about65%, at least about 70%, at least about 75%, at least about 80%, atleast about 85%, at least about 90%, about 60% to about 95%, about 65%to about 95%, or about 70% to about 90%. In some embodiments, the highefficiency nebulizer is characterized by an RF of at least about 80% orabout 70% to about 90%.

The Emitted Dose (ED), or Delivered Dose (DD), of drug administered to apatient is the portion of volume of liquid filled into the nebulizer,i.e. the fill volume, which is actually emitted from the mouthpiece ofthe device. The difference between the nominal dose and the ED is theamount of volume lost primarily to residues, i.e. the amount of fillvolume remaining in the nebulizer after administration, or is lost inaerosol form. The ED of the muscarinic antagonist is to be tested undersimulated breathing conditions using a standardized bench setup, whichare known to one of skill in the art. In some embodiments, the ED of themuscarinic antagonist of the present invention is at least about 30%, atleast about 35%, at least about 40%, at least about 45%, at least about50%, at least about 55%, at least about 60%, about 30% to about 60%,about 30% to about 55%, about 30% to about 50%, about 30% to about 40%,about 30% to about 75%, about 40% to about 70%, or about 45% to about60%. The Respirable Dose (RD) is an expression of the delivered mass ofdrug contained within emitted droplets from a nebulizer that are smallenough to reach the lung of a patient. The RD is determined bymultiplying the ED by the RF, and can be readily determined using therespective ED and RE values provided herein.

The output rate is the speed at which API is administered from theinhalation device. In some embodiments, administration of the muscarinicantagonist with the high efficiency nebulizer provides an output rate ofAPI of at least about 2 times, 3 times or 4 times the output rateachievable with a conventional nebulizer. For example, where themuscarinic antagonist is glycopyrrolate, in some embodiments the outputrate is at least about 120 μg/min, at least about 150 μg/min, at leastabout 200 μg/min or at least about 200 μg/min to at least about 5,000μg/min. In some embodiments, administration of glycopyrrolate with thehigh efficiency nebulizer provides an output rate of API of at leastabout 120 μL/min, at least about 150 μL/min, at least about 200 μL/minor at least about 200 μL/min to at least about 5,000 μL/min.

The Respirable Dose Delivery Rate (RDDR) is the speed at which arespirable dose of the drug is nebulized, administered, and delivered toa patient's lungs. RDDR, measured as a function of μg/min, is determinedby dividing the RD (in μg) by the amount of time necessary forinhalation. The amount of time necessary for inhalation is measured asthe amount of time from the first moment of administration of theemitted droplet from the nebulizer until the emitted droplet ofrespirable diameter is delivered to the lung, as measured using astandardized bench setup simulating breathing conditions. In someembodiments, administration of the muscarinic, antagonist to the patientwith the high efficiency nebulizer provides a respirable dose deliveryrate (RDDR) of at least about 2 times, 3 times or 4 times the deliveryrate achievable with a conventional nebulizer. Where the muscarinicantagonist is glycopyrrolate, in some embodiments the RDDR is at leastabout 100 μg/min, at least about 150 μg/min, at least about 200 μg/min,about 100 μg/min to about 5,000 μg/min, about 150 μg/min to about 4,000μg/min or about 200 μg/min to about 3,500 μg/min. In some embodiments,administration of the glycopyrrolate to the patient with an aqueousinhalation device provides an RDDR of at least about 100 μg/min or about100 μg/min to about 5,000 μg/min.

EXAMPLES

The following ingredients, processes and procedures for practicing thesystems and methods disclosed herein correspond to that described above.The procedures below describe some embodiments of methods of delivery ofa nebulized long-acting cholinergic antagonist aqueous solution (as amonotherapeutic agent), or in combination with a nebulizedβ2-adrenoceptor aqueous solution (in combination therapy) as describedherein and pharmacokinetic profiles thereof. Methods, materials, orexcipients which are not specifically described in the followingexamples are within the scope of the invention and will be apparent tothose skilled in the art with reference to the disclosure herein.

Example 1: Single-Dose, Dose Escalation Study to Assess GlycopyrrolateInhalation Solution (GIS) Using a High Efficiency Nebulizer in Patientswith COPD

Objectives:

The objectives of the study were as follows: Primary: To assess thesafety and tolerability of single ascending doses of glycopyrrolateinhalation solution when administered using a high efficiency nebulizerin patients with COPD. Secondary: (1) To assess and to compare themagnitude and duration of bronchodilator response in patients with COPDfollowing single doses of glycopyrrolate inhalation solution whenadministered using a high efficiency nebulizer and a conventional jetnebulizer; and (2) To assess the pharmacokinetic (PK) profile of aninhaled glycopyrrolate solution formulation.

Methodology:

This two part study was a two-center, single dose, dose-escalation studyin patients with COPD of 40-75 years of age. There were 12 subjectsincluded in the study.

Part 1 was an open label study to assess the safety, tolerability, PKprofile and bronchodilator response following single doses ofglycopyrrolate inhalation solution when administered via a highefficiency nebulizer. Subjects were studied in two cohorts in parallel.Prior to treatment, subjects received a thorough medical examination(Screening Visit). A Treatment Period consisted of two doses ofglycopyrrolate inhalation solution being administered in the firstcohort in a dose-escalation manner at two separate visits (TreatmentVisits), and three doses being administered in the second cohort inthree separate visits (Treatment Visits), with a washout period of 5 to12 days between doses for both cohorts. After identifying an effectivedose of glycopyrrolate inhalation solution that provided 24 hours ofbronchodilation when using a high efficiency nebulizer in Part 1, allsubjects entered Part 2 of the study and received, in a randomized,double-blind manner, a single dose of either glycopyrrolate inhalationsolution (as determined in Part 1) or placebo via a conventional jetnebulizer. The high efficiency nebulizer tested was the eFlow® (PARI,Germany). The conventional jet nebulizer tested was a DeVilbiss 800D.

Study procedures during each Treatment Period included serial spirometry(including FEV₁, FVC and PEFR) pre-dose and immediately following dosing(within 5 minutes) and 15, 30 60, 90 minutes and 2, 4, 6, 8, 10, 12, 15,23, 24, 27, and 30 hours post-dose. Blood samples were obtained todetermine plasma GP concentrations at pre-dose and 5, 15, 30, 45 minutesand 1, 2, 4, 6, 8 and 12 hours post-dose. Vital signs and 12-leadelectrocardiogram were obtained at pre-dose and 30 and 60 minutes and 2,4, 8, 12, 24 and 30 hours post-dose. Clinical labs were done at theScreening Visit and within 7 days following the last study treatment(Safety Follow-up Visit).

Study Treatments, Dose and Mode of Administration:

Part 1 (n=12): Subjects were randomly allocated to one of 2 cohortsrunning in parallel.

Cohort 1 (n=6): 1. Glycopyrrolate inhalation solution (GIS) 25 μg/0.5 mLoral inhalation via eFlow; 2. GIS 200 μg/0.5 mL oral inhalation viaeFlow.

Cohort 2 (n:=6): 1. GIS 75 μg/0.5 mL oral inhalation via eFlow; 2. GIS500 μg/0.5 mL oral; 3. GIS 1000 μg/0.5 mL oral inhalation via eFlow.

Part 2 (n=12): All subjects who participated in Part 1 were included.Glycopyrrolate inhalation solution (200 mcg (μg) dose (selected fromPart 1) or placebo in 2 mL solution formulation via the conventional jetnebulizer.

Assessments

The primary efficacy variable was serial spirometry throughout the 36hour period after dosing. The spirometry assessments include forcedexpiratory volume in one second (FEV₁), forced vital capacity (FVC),peak expiratory flow rate (PEFR), FEV₁% of predicted normal.

The PK parameters to be evaluated for plasma glycopyrrolate are maximumconcentration (C_(max)), time to maximum concentration (T_(max)),terminal elimination half-life (T_(1/2)), area under the plasmaconcentration-time curve from time=0 to time of last measurable drugconcentration (AUC_(0-t)), and area under the plasma concentration-timecurve from time=0 to infinity (AUC_(0-inf)).

Safety parameters include adverse events (AEs) including assessment ofdry mouth, and changes in vital signs, 12-lead ECG (including QTcinterval), and clinical laboratory tests.

The results are summarized in Table 1-1 and in FIG. 1 through FIG. 8.

In part 1, subjects in Cohort 1 received 25 μg and, after the washoutperiod, 200 μg of glycopyrrolate with the high efficiency nebulizer,while Cohort 2 received 75 μg, 500 μg and 1000 μg doses ofglycopyrrolate separated by washout periods. Based on the results ofpart 1, 200 μg of glycopyrrolate was chosen as the comparator forcarrying into part 2 of the study.

In part 2, the two cohorts were randomized to a placebo group and an“active” group. The placebo group received normal saline and the“active” group received 200 μg of glycopyrrolate, both via theconventional jet nebulizer. The results of this study are depicted inthe line graph in FIG. 3, where the 200 μg eFlow® high efficiencynebulizer results are also depicted for comparison. As can be seen inFIG. 3, the 200 μg dose of glycopyrrolate administered with theconventional jet nebulizer did not provide clinically meaningfulimprovement in FEV₁ at 12 hours and beyond, whereas the same doseadministered with the high efficiency nebulizer provided clinicallyrelevant improvements in FEV₁ up to and beyond the 24 hour time point.Also, the glycopyrrolate dose administered with the high efficiencynebulizer provided a mean improvement in peak lung function (peak FEV₁)of about 45 mL compared to the same glycopyrrolate dose administered inthe conventional jet nebulizer,

FIG. 4 is a graph comparing lung function response (FEV1% change frombaseline) over a time course of 30 hours for 200 μg of glycopyrrolateadministered with a high efficiency nebulizer (left-most bar at eachtime point), 200 μg of glycopyrrolate administered with the conventionaljet nebulizer (right-most bar at each time point), and placebo (saline)administered with the conventional jet nebulizer (middle bar at eachtime point). The glycopyrrolate dose administered with the highefficiency nebulizer provided improvement in lung function of greaterthan 10% in FEV1 above baseline at the 24 hour time point, whereas thesame dose administered with the conventional jet nebulizer failed toachieve an increase in FEV1 above baseline greater than 10% at the 12 hrtime point and beyond.

As shown in FIG. 1, which is a bar graph comparing the meanplacebo-adjusted 24-hour (trough) change in FEV1 (L) for the 200 μg doseof glycopyrrolate delivered via the high efficiency nebulizer to the 200μg dose delivered via the conventional jet nebulizer, the highefficiency nebulizer provided significantly improved improvement in lungfunction at 24 hours post-administration of glycopyrrolate. This is thefirst known disclosure of a clinically meaningful improvement in lungfunction greater than 12 hours for any solution formulation ofglycopyrrolate at any dose.

Administration of glycopyrrolate with a high efficiency nebulizerprovides prolonged efficacy across a broad dosage range. As can be seenin FIG. 2, which is a graph comparing the mean placebo-adjusted 24-hour(trough) FEV1 (L) obtained by administering 25 μg, 75 μg, 200 μg, 500 μgand 1000 μg of glycopyrrolate with a high efficiency nebulizer (left 5bars) and 200 μg with the conventional jet nebulizer (right bar), thehigh efficiency nebulizer provided significant improvement in lungfunction compared to baseline at 24 hours post-administration ofglycopyrrolate for each of 75 μg, 200 μg, 500 μg and 1000 μgglycopyrrolate doses. There is no known teaching in the art thatadministration of a drug with a high efficiency nebulizer will result ingreater duration of efficacy.

Another measure of improved lung function is the baseline- andplacebo-adjusted area under the FEV₁ change curve from 0-24 hours(FEV₁AUC₀₋₂₄). FIG. 5 compares the area under the FEV₁ change (L, abovebaseline) curve from 0-24 hours (FEV₁ AUC₀₋₂₄) obtained by administering25 μg, 75 μg, 200 μg, 50 μg and 1000 μg of glycopyrrolate with a highefficiency nebulizer (left 5 bars); and placebo and 200 μg ofglycopyrrolate with the conventional jet nebulizer (right 2 bars). TheFEV₁ AUC₀₋₂₄ results are shown in units of L·hr. As can be seen in FIG.5, glycopyrrolate delivered with a high efficiency nebulizer producedsignificantly improved lung function over the period from 0-24 hours.

FIG. 6 is a graph comparing the area under the FEV₁ change (L, abovebaseline) curve from 0-12 hours (AUC_(0-12 hrs)) obtained byadministering 25 μg, 75 μg, 200 μg, 500 μg and 1000 μg of glycopyrrolatewith a high efficiency nebulizer (left 5 bars); and placebo and 200 μgof glycopyrrolate with a conventional jet nebulizer (right 2 bars). TheAUC₀₋₁₂ results are shown in L·hr. The FEV₁ AUC values for the 25 μgdose delivered by the high efficiency nebulizer achieved a similarrobust magnitude of FEV₁ improvement as the dose delivered by theconventional jet nebulizer over the first 12 hours post-administration.The FEV₁ AUC values for the 75 μg, 200 μg, 500 μg and 1000 μg ofglycopyrrolate delivered with a high efficiency nebulizer weresignificantly higher compared to the FEV₁ AUC value for the 200 μg dosedelivered with the conventional jet nebulizer.

The improved duration of therapeutic activity of glycopyrrolateadministered with a high efficiency nebulizer, as compared to theconventional jet nebulizer, can best be observed in FIG. 7, whichcompares the area under the FEV₁ change (L, above baseline) curve from12-24 hours (AUC₁₂₋₂₄) obtained by administering 25 μg, 75 μg, 200 μg,500 μg and 1000 μg of glycopyrrolate with a high efficiency nebulizer(left 5 bars); and placebo and 200 μg of glycopyrrolate with aconventional jet nebulizer (right 2 bars). The FEV₁ AUC₁₂₋₂₄ results areshown in units of L·hr. As can be seen in FIG. 7, at everyglycopyrrolate dose tested, the improvement in lung function withglycopyrrolate administered with a high efficiency nebulizer wassignificantly greater between 12 and 24 hours than with the dose ofglycopyrrolate administered with the conventional jet nebulizer.

In order to better understand the mechanism by which administration ofglycopyrrolate with a high efficiency nebulizer improves lung function,blood plasma concentration levels of glycopyrrolate were obtained forthe 200 μg high efficiency nebulizer and 200 μg conventional nebulizerstudy arms. Table 1-3 summarizes the pharmacokinetic (PK) measurementsobtained. FIG. 8 is a line graph comparing glycopyrrolate blood plasmaconcentrations during the first two hours after administration of 200 μgglycopyrrolate with a high efficiency nebulizer (upper line) and 200 μgglycopyrrolate with the conventional jet nebulizer (lower line). As canbe seen in FIG. 8, in addition to exhibiting a later Tmax and aconsiderably higher Cmax, the high efficiency nebulizer (HEN) arm alsoexhibited significantly longer elimination. Without wishing to be boundby theory, it appears that this may be evidence of a depot effect,whereby the enhanced deposition of glycopyrrolate in the lungs, andparticularly in the periphery of a diseased COPD lung which ischaracterized by poor mucociliary clearance, may result in prolongedduration of bronchodilation.

One property of administration of glycopyrrolate with a high efficiencynebulizer is an enhancement in glycopyrrolate blood plasma AUC relativeto Cmax. As can be seen in Table 1-1, the ratio of AUC/Cmax forglycopyrrolate administered with a high efficiency nebulizer is muchgreater than the AUC/Cmax for glycopyrrolate administered with theconventional jet nebulizer. Achievement of a AUC/Cmax ratio greater than0.5 hrs, or 1 hr, or 1.5 hrs, or 2 hrs in combination with a totalAUC₀₋₄ greater than 100 μg/mL·h, or 200 μg/mL·h is believed to beimportant for achievement of a 24 hour duration of activity for asolution formulation of glycopyrrolate.

TABLE 1-1 PK Values for Administration of Glycopyrrolate with HighEfficiency and Conventional Jet Nebulizers Pharmacokinetic HighEfficiency Conventional Value Nebulizer 200 μg Nebulizer 200 μg Cmax 177pg/mL 76 pg/mL Tmax 11.6 min 8.2 min AUC_((0-t)) 429 pg/mL · h 26 pg/mL· h AUC_((0-inf)) 615 pg/mL · h 70 pg/mL · h Cmax/AUC_((0-t)) 0.41/h2.92/h AUC_((0-t))/Cmax 2.42 h 0.35 h t ½ 4.1 h 0.9 h t ½_((0-60 min))72 min 46 min

As can be seen in Table 1.1, the Tmax is longer (about 12 min. vs about8 min.) for glycopyrrolate when administered with the high efficiencynebulizer than with the conventional jet nebulizer, demonstrating aslower elimination of glycopyrrolate from the lung/airway compartmentinto the systemic blood when using the high efficiency nebulizer.Additional evidence of a slower elimination of glycopyrrolate from thelung/airway compartment when delivered by a high efficiency nebulizer isthat, for the first 60 minutes post-dosing, the plasma eliminationhalf-life of glycopyrrolate was much greater (prolonged) as compared toadministration of the same dose with a conventional jet nebulizer (72min. vs 46 min.).

Example 2: Randomized, Double-Blind, Placebo-Controlled Cross-Over,Single Dose Study

At least about thirty (30) adult human COPD patients of ages >45 yearsare randomized to one of six treatment groups: (1) 2.5 μg glycopyrrolateadministered with a high efficiency nebulizer; (2) 50 μg ofglycopyrrolate administered with a high efficiency nebulizer; (3) 100 μgof glycopyrrolate administered with a high efficiency nebulizer; (4) 200μg of glycopyrrolate administered with a high efficiency nebulizer; (5)500 μg of glycopyrrolate administered with a high efficiency nebulizer;(6) placebo administered with a high efficiency nebulizer.

Lung function is determined by spirometry, which measures e.g. FEV₁ andother suitable spirometry parameters. Spirometry is conductedimmediately before and at predetermined intervals followingadministration of the glycopyrrolate to the patients. Additionally, thepatients will be monitored for any adverse events, as well as for vitalsigns and electrocardiogram.

A goal of this study is to verify that glycopyrrolate administered tohuman patients with a high efficiency nebulizer at the tested dosesproduces in a patient or population of patients a therapeutic effect(i.e. at least one spirometry measurement, e.g. trough FEV₁, is at least10% above baseline for a significant period of time, e.g. at least 24hours.)

Another goal of this study is to verify that glycopyrrolate administeredto human patients with a high efficiency nebulizer produces in a patientor population of patients a suitable adverse event profile.

Example 3: Aerosol Characterization of Glycopyrrolate InhalationSolution in a High Efficiency Nebulizer and a Conventional Jet NebulizerObjective

The object of the study was to determine and compare the drug deliveryefficiency of two different nebulizer systems, a high efficiencynebulizer and a conventional jet nebulizer, using a glycopyrrolateinhalation solution (GIS). Droplet size and respirable fraction of theaerosol were measured by laser diffraction, while delivered dose,nebulization time and nebulizer residue were assessed by breathsimulation using a standard adult breathing pattern.

Summary

Two different nebulizers were characterized by laser diffraction andbreath simulation. An innovative new vibrating membrane, high efficiencynebulizer (PARI eFlow® 30 L), and a commonly used conventional jetnebulizer (DeVilbiss 800D). 12 laser diffraction and 12 breathsimulation experiments in total were carried out. The parameters of DD,nebulization time, MMD, GSD, RD<5 μm and RDDR were determined upon thesemeasurements.

The high efficiency nebulizer generated droplets of a mass mediandiameter (MMD) of around 3.5 μm and a geometric standard deviation (GSD)of 1.55 compared to the MMD and GSD obtained from the conventional jetnebulizer (3.6 μm, 2.94).

To determine the delivered dose (DD), breath simulator experiments wereperformed with an adult breathing pattern.

The respirable dose (RD) is calculated by multiplying the DI), obtainedin breath simulation experiments, by the percentage of aerosol particlesless than 5 μm (RD<5 μm) determined by laser diffraction.

Materials and Methods

The drug formulation was a 2 mg/mL, glycopyrrolate solution (GIS). Thissolution was tested at the following quantities (mg) and volumes (mL):High efficiency nebulizer @ 1 mg/0.5 mL, and conventional jet nebulizer@ 4 mg/2 mL.

Breath simulation tests were conducted and a breath simulator with adultbreathing pattern was conducted (500 mL tidal volumes, 15 breaths/min,inhalation/exhalation ratio 50:50).

The nebulizers were equipped with expiratory filters and connected viaan inspiratory filter to the breathing simulator. The inspiratory filterwas changed after the first minute, the second filter remained until theend of nebulization. The end of the nebulization was reached for thehigh efficiency nebulizer when the nebulizer switched off automatically;for the jet nebulizer, the end of nebulization was achieved one minuteafter sputtering began.

Laser diffraction was used to assess the geometric droplet sizedistribution with a Malvern MasterSizerX® laser diffraction measurementdevice. Airflow was 15 L/min±0.1 L/min; temperature was 23° C.±2° C.;relative humidity was 50%±5%. The parameters obtained with laserdiffraction were: mass median diameter of the droplets (MMD), respirablefraction (RF), geometric standard deviation (GSD), and total output rate(TOR).

The calculated parameters were respirable dose (RD) and respirable drugdelivery rate (RDDR).

The results of this in vitro aerosol characterization are presented inTable 5-1.

TABLE 5-1 In vitro aerosol characterization of a high efficiencynebulizer and a conventional jet nebulizer. High Efficiency ConventionalJet Nebulizer Nebulizer MMD/MMAD 3.5 μm 3.6 μm GSD 1.6 μm 2.9 μm DD 66%11% RF < 5 μm 80% 67% RD < 5 μm 52.6%   7.5%  RDDR < 5 μm 39%  2%

CONCLUSION

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended, thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

1-38. (canceled)
 39. A composition for administration with a highefficiency nebulizer, comprising a concentrated, preservative-free,pH-adjusted solution formulation of a muscarinic antagonist.
 40. Thecomposition of claim 39, wherein the composition is an aqueous solutionof glycopyrrolate having a volume of about 0.5 mL to about 1.5 mL, aglycopyrrolate concentration of about 25 μg/mL to about 250 μg/mL, and apH of about 3 to about 5, wherein the solution is free of otherbronchodilating agents.
 41. The composition of claim 40, wherein theglycopyrrolate concentration is about 25 μg/mL and/or the volume isabout 1 mL and/or the pH is about 3 to about
 5. 42. A method of treatinga respiratory condition in a subject comprising administering to thesubject a composition of claim
 39. 43. The method of claim 42, whereinthe respiratory condition is chronic bronchitis, chronic obstructivepulmonary disease (COPD), or emphysema.
 44. A method of treating arespiratory condition in a subject comprising administering to thesubject a composition of claim
 40. 45. The method of claim 44, whereinthe glycopyrrolate concentration is about 25 μg/mL and/or the volume isabout 1 mL and/or the pH is about 3 to about
 5. 46. The method of claim44, wherein the composition comprises an aqueous solution ofglycopyrrolate having a volume of about 1.0 mL, a glycopyrrolateconcentration of about 25 μg/mL, and a pH of about 3 to about 5, whereinthe solution is free of other bronchodilating agents and issubstantially free of preservatives.
 47. The method of claim 46, whereinsaid aqueous solution further comprises citric acid or apharmaceutically acceptable salt thereof.
 48. The method of claim 44,wherein the respiratory condition is chronic bronchitis or emphysema.49. The method of claim 48, wherein the glycopyrrolate concentration isabout 25 μg/mL and/or the volume is about 1 mL and/or the pH is about 3to about
 5. 50. The method of claim 48, wherein the compositioncomprises an aqueous solution of glycopyrrolate having a volume of about1.0 mL, a glycopyrrolate concentration of about 25 μg/mL, and a pH ofabout 3 to about 5, wherein the solution is free of otherbronchodilating agents and is substantially free of preservatives. 51.The method of claim 50, wherein the aqueous solution further comprisescitric acid or a pharmaceutically acceptable salt thereof.
 52. A methodof treating a patient having chronic obstructive pulmonary disease(COPD), comprising administering to the patient, with a high efficiencynebulizer, a nominal dose of a composition comprising a muscarinicantagonist that provides the patient with a therapeutic effect at leastabout 24 hours after administering the muscarinic antagonist to thepatient.
 53. The method of claim 52, wherein the muscarinic antagonistis glycopyrrolate.
 54. The method of claim 53, wherein theglycopyrrolate concentration is about 25 μg/mL and/or the volume of thecomposition is about 1 mL and/or the pH of the composition is about 3 toabout
 5. 55. The method of claim 52, wherein the composition comprisesan aqueous solution of glycopyrrolate having a volume of about 1.0 mL, aglycopyrrolate concentration of about 25 μg/mL, and a pH of about 3 toabout 5, wherein the solution is free of other bronchodilating agentsand is substantially free of preservatives.
 56. The method of claim 55,wherein said aqueous solution further comprises citric acid or apharmaceutically acceptable salt thereof.
 57. A method for themaintenance treatment of severe chronic obstructive pulmonary disease(COPD) in a patient, the method comprising: (a) administering to thepatient, with a high efficiency nebulizer, a first nominal dose of afirst aqueous inhalation solution comprising less than about 80 μg ofglycopyrrolate, and free of other bronchodilating agents; and (b)administering to the patient, with a high efficiency nebulizer, a secondnominal dose of a second aqueous inhalation solution comprising lessthan about 80 μg of glycopyrrolate, and free of other bronchodilatingagents; wherein the combination of the first and second nominal dosesprovides the patient with a therapeutic effect at least 24 hours afteradministering the first nominal dose to the patient; and wherein thefirst and second nominal doses are administered to the patient in a24-hour period.
 58. The method of claim 57, wherein the glycopyrrolateconcentration is about 25 μg/mL.